Heller v. Secretary of Health and Human Services ( 2022 )

In the United States Court of Federal Claims
No. 15-792
(Filed: 31 October 2022 *)
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HEATHE HELLER and JENNA HELLER, *
as parents of H.H., a Minor, *
*
Petitioners, * Vaccine Act; Off-Table; Aicardi-Goutières
* Syndrome; AGS; Type I Interferonopathy;
v. * Significant Aggravation; Genetic Mutation;
* Loving; Pentacel.
SECRETARY OF HEALTH AND HUMAN *
SERVICES, *
*
Respondent. *
*
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Margaret M. Guerra, Attorney at Law, Fort Worth, TX, for petitioners.
Tyler King, Vaccine/Torts Branch, Civil Division, U.S. Department of Justice,
Washington, DC, for respondent.
OPINION AND ORDER
HOLTE, Judge.
This case involves the injury of a child with a suspected pre-existing genetic mutation.
Congress designed the Vaccine Act as part of “the Nation’s efforts to protect its children by
preventing disease.” Cloer v. Sec’y of Health & Hum. Servs., 654 F.3d 1322, 1325 (Fed. Cir.
2011) (quoting H.R. Rep. No. 99-908, at 4 (1986)). “[W]hile most of the Nation’s children enjoy
a greater benefit from immunization programs, a small but significant number have been gravely
injured.” Id. Congress created the Vaccine Program to “compensate injured persons quickly and
fairly” for injuries “either presumed or proven to be causally connected to vaccines.” Id.Petitioners Heathe Heller and Jenna Heller (“petitioners”), on behalf of their son, H.H.,
filed a petition for compensation under the National Vaccine Injury Compensation Program, 42
U.S.C. § 300aa-10, et seq. See Pet., ECF No. 1. Petitioners allege H.H.’s 15-month vaccinations
caused or significantly aggravated H.H.’s degenerative neurological disorder. Id. The Special
Master, in her Decision for Entitlement, denied petitioners’ request because petitioners were
*
This opinion was initially filed under seal on 13 October 2022 pursuant to Vaccine Rule 18(b) of the Rules of the
Court of Federal Claims. The Court provided the parties 14 days to submit proposed redactions, if any, before the
opinion was released for publication. Neither party proposed redactions. This opinion is now reissued for
publication in its original form.
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unable to preponderantly establish the vaccinations caused or significantly aggravated H.H.’s
injury. SM Dec. 74, ECF No. 121. Petitioners filed a motion for review with an accompanying
memorandum asking the Court for review of the Special Master’s decision denying the petition.
See Mot. for Review, ECF No. 122; Mot. for Review Mem., ECF No. 123. According to
petitioners, the Special Master erroneously diagnosed H.H. with a genetically caused
Aicardi–Goutières Syndrome (“AGS”) or AGS-like type I interferonopathy, altering the
Loving/Althen causation in fact analyses against the significant evidence proffered by petitioners.
Mot. for Review Mem. at 1. For the following reasons, the Court GRANTS petitioners’ motion
in part, VACATES the Special Master’s decision in part, and REMANDS this case to the
Special Master for further proceedings consistent with this opinion.
I. Petitioners’ Medical History and the Vaccination
As the basic facts have not changed significantly from petitioners’ original claim to their
appeal, the Court’s recitation of the background facts draws from the Special Master’s Decision
of Entitlement (“SM Dec.”). 1 H.H. was born on 14 July 2012. Pet’rs’ Ex. 48.1, ECF No. 40-1
(Birth Certificate). Except for an abnormal newborn screen indicating a very long-chain
acyl-CoA dehydrogenase (“VLCAD”) deficiency, a condition in which the body is unable to
properly break down certain fats into energy, H.H.’s well-child visits were normal, and H.H. was
meeting developmental milestones. Pet’rs’ Ex. 49.2 at 7–34, ECF No. 40-2 (Dr. Hollis Notes,
pages 1–42). On 29 July 2013, when H.H. was a year old, Dr. Hollis, a pediatrician, saw H.H.
for a sick-child visit due to a fever and nasal congestion. Id. at 36. On 13 September 2013, Ms.
Heller called H.H.’s pediatrician’s office because H.H. was not walking, and his right foot turned
inward. Id. at 37. The office suggested the problem be discussed further at H.H.’s upcoming
15-month appointment. Id.
At his 15-month well visit, Dr. Hollis noted H.H. was meeting all development
milestones, and there were no physical abnormalities. Id. at 1–2. H.H. also received the
influenza and pneumonia vaccines at the 15-month appointment. Id. He was supposed to
receive the DTaP-IVH-Hib (Pentacel) vaccine as well, but the office was out of Pentacel, so
H.H. returned on 23 October 2013 to receive the vaccine. Id. at 3. On 11 November 2013, H.H.
was fussy, running a fever, and had decreased energy levels. Pet’rs’ Ex. 49.2 at 41. Dr. Hollis
noted H.H. had regressed in the last month, explaining he stopped crawling, lost interest in
playing with toys, and threw food. Id. At the conclusion of the appointment, H.H. was
diagnosed with developmental delay and acute pharyngitis and was referred to neurology for
evaluation. Id. The next day, H.H. visited Dr. Crawford, a geneticist, who noted elevated
transaminase levels and developmental delays. Pet’rs’ Ex. 50.4 at 1–2, ECF No. 40-4 (Dr.
Crawford Notes, pages 1–27). Dr. Crawford ordered genetic and metabolic workups as well as a
magnetic resonance imaging (“MRI”) and recommended physical and speech therapy. Id. at 2.
On 14 November 2013, H.H. was admitted to the hospital where physicians found “significant
dystonic posturing of the lower extremities.” Pet’rs’ Ex. 51.6 at 5, ECF No. 40-6 (Cook’s
Radiology Records). H.H. was treated and discharged on 16 November 2013. Id.
1
In describing the background of petitioners’ claim, the Court refers primarily to the special master’s factual
background as recited in the decision for entitlement. See SM Dec. at 5–27. Petitioners do not assert error in the
facts as stated by the Special Master, but rather challenge the legal conclusions drawn from those facts. See
generally Mot. for Review.
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On 22 November 2013, Dr. Aalbers, a neurologist, saw H.H. and noted H.H. had lost
meaningful use of his right hand since his discharge on 16 November 2013. Pet’rs’ Ex. 52.7 at 9,
ECF No. 40-7 (Dr. Aalbers Notes, pages 1–34). Dr. Aalbers believed H.H. had “rapidly
progressive ascending dystonia with encephalopathy” and was concerned with mitochondrial
disease. Id. at 11. On 23 November 2013, H.H. underwent genetic testing, and the results did
not show any “deletions or duplications of known or potential clinical significance.” Pet’rs’ Ex.
50.5 at 61, ECF No. 40-5 (Dr. Crawford Notes, pages 26–66). On a 3 December 2013 visit, Dr.
Aalbers definitively diagnosed H.H. with “rapidly progressive dystonia and encephalopathy”
with “concern for possible Aicardi-Goutières [syndrome (‘AGS’).]” Pet’rs’ Ex. 52.7 at 28. To
confirm a diagnosis, Dr. Aalbers arranged for human immunodeficiency virus (“HIV”) testing,
ordered a second round of neurotransmitter studies, and referred H.H. to Dr. Crawford for
additional genetic testing. Id. On 3 December 2013, Dr. Crawford noted H.H.’s neopterin and
tetrahydrobiopterin were significantly elevated, and the lab stated, “only Aicardi-Goutieres
syndrome and HIV infection would cause such high values.” Dr. Crawford Notes, pages 1–27 at
12. Dr. Crawford noted H.H. “does not have [a] typical presentation of AGS[;] . . . however,
there are milder presentation[s] of this syndrome . . . . Therefore, this disorder remains on our
differential.” Id. She received permission from H.H.’s family to contact an AGS expert in
England, Dr. Yanick Crow, and recommended intensive therapies. Id.
On 18 December 2013, H.H. visited Dr. Richard Roberts, a neurosurgeon, for a
consultation regarding H.H.’s tethered spinal cord, revealed after an MRI showed “a thickened
and fat infiltrated filum terminale.” Pet’rs’ Ex. 53.9 at 7, ECF No. 40-9 (Dr. Roberts Notes,
pages 1–10). H.H. underwent surgery to release his tethered spinal cord the next day, and the
cerebrospinal fluid taken during surgery showed “remarkably high elevations of biopterin and
neopterin”—the highest levels Dr. Aalbers had ever seen. Id. at 7–8; Pet’rs’ Ex. 55.2 at 1, ECF
No. 41-2 (Drs. Aalbers and Cantu Notes, pages 1–20). Dr. Aalbers noted the differential
diagnosis in a patient with high levels of neopterin, elevated liver enzymes, and dystonia was
likely “Aicardi-Goutières syndrome,” even though the genetic disorder was incredibly rare. Id.
at 1, 4. Dr. Aalbers ordered additional testing in the hospital which showed an abnormal
electroencephalogram “consistent with Aicardi-Goutieres syndrome.” Id. at 3–4. While still in
the hospital, Lori Thompson, a Certified Pediatric Nurse Practitioner (“CPNP”), saw H.H.
regarding his elevated transaminases. Pet’rs’ Ex. 54.1 at 1, ECF No. 41-1 (Dr. Thompson Notes,
pages 1–6). Nurse Thompson noted AGS was a concern and H.H. would undergo neurological
and gastroenterological testing to reevaluate his liver transaminases. Id. On 17 January 2014,
Dr. Samson Cantu, a gastroenterologist, saw H.H. for abnormal liver enzymes, and the testing
ordered revealed low globulin, a high albumin/globulin ratio, low bilirubin, high aspartate
transaminase (“AST”), and high alanine transaminase (“ALT”) levels. Pet’rs’ Ex. 55.2 at 9;
Pet’rs’ Ex. 80.8 at 8, ECF No. 45-8 (Dr. Cantu Notes, pages 1–68).
On 4 February 2014, Dr. Marks, a pediatric neurologist, reviewed the results of the
neurological and genetic testing and indicated AGS was the likely diagnosis but was awaiting
genetic confirmation. Pet’rs’ Ex. 56.3 at 4, ECF No. 41-3 (Dr. Marks Notes, pages 1–45). Dr.
Crawford, the geneticist, saw H.H. the same day and noted H.H. “appears to have a later-onset
presentation for AGS,” but genetic testing was ongoing in England. Pet’rs’ Ex. 50.4 at 23–24.
On 6 March 2014, H.H. received the results of his genetic testing, which indicated one
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significant mutation, a VLCAD deficiency in the gene acyl-CoA dehydrogenase very long chain
(“ACADVL”). Pet’rs’ Ex. 50.5 at 40. Dr. Marks noted H.H. could have “possible AGS” but
with an unidentified genetic marker. Pet’rs’ Ex. 56.3 at 18.
On 25 March 2014, after repeat testing, H.H.’s neopterin was extremely elevated, and Dr.
Hyland, Director of Labcorp’s Department of Neurochemistry Medical Neurogenetics
Laboratories, interpreted the testing and noted the findings were consistent with a diagnosis of
AGS. Pet’rs’ Ex. 56.11 at 360–61, ECF No. 41-11 (Dr. Marks Notes, pages 342–387). On 23
April 2014, Dr. Cantu, the gastroenterologist, noted H.H. had an “extensive work-up by
neurology with unclear diagnosis, although it has been suggested he may have a variant of
Aicardi.” Pet’rs’ Ex. 61.8 at 13, ECF No. 42-8 (Dr. Marks Notes, pages 1–26). On 24 April
2014, Dr. Marks, the pediatric neurologist, diagnosed H.H. with “[p]rogressive encephalopathy
and dystonia with loss of milestones and worsening dystonia[,] [and] [i]nterferonopathy with
elevated neopterin clinically suggestive of Aicardi-Goutière[s] [s]yndrome but with negative
genetic testing.” Pet’rs’ Ex. 56.10 at 328, ECF No. 41-10 (Dr. Marks Notes, pages 297–341).
Dr. Marks recommended intravenous immune globulin (“IVIG”) treatment, which H.H. began in
June. Id. at 329. On 3 November 2014, H.H.’s testing showed elevated Immunoglobulin G
(“IgG”) serum, elevated indocyanine green (“ICG”)/albumin ratio, high neopterin, and high
tetrahydrobiopterin. Id. at 323–24. The nurse who completed the pre-procedure nursing record
on behalf of Dr. Marks noted H.H. suffered from “autoimmune response to vaccines.” Pet’rs’
Ex. 56.6 at 106, ECF No. 41-6 (Dr. Marks Notes, pages 96–145).
On 20 March 2015, H.H. visited the Myelin Disorders Clinic at Children’s National
Hospital in Washington, DC and saw Dr. Adeline Vanderver, the director of the clinic, who
planned to follow up with Dr. Crow, the clinical scientist in England specializing in AGS
research, to discuss H.H.’s suspected heritable interferonopathy. Pet’rs’ Ex. 81.9 at 6, ECF No.
45-9 (Dr. Vanderver Notes, pages 1–10). On 4 March 2016, H.H. saw Dr. Marc Mazade, an
infectious disease specialist, who noted H.H. was “diagnosed with encephalitis of an
autoimmune nature presumably due to vaccinations two weeks previously.” Pet’rs’ Ex. 95 at 54,
56–57, ECF No. 61 (Medical Records). On 15 November 2016, H.H. saw Dr. Abigail Collins, a
pediatric neurologist, for treatment with medical marijuana. Pet’rs’ Ex. 98, ECF No. 93-2
(Medical Records). On 8 December 2016, H.H. underwent hip surgery to alleviate hip tightness
associated with his neuromuscular hip dysplasia. Pet’rs’ Ex. 95 at 199.
On 26 June 2017, Dr. Marks found H.H. had elevated glucose levels, but his neopterin
and tetrahydrobiopterin levels were normal. Pet’rs’ Ex. 95 at 77. An MRI showed H.H. had lost
white matter over the past three years. Id. at 147. On 9 July 2017, H.H. visited the emergency
room with complaints of seizures. Id. at 105. Doctors were unable to determine the origin of the
seizure. Id. at 135. H.H. was discharged on 11 July 2017, and the discharge summary noted Dr.
Marks would seek approval for an experimental use drug for AGS. Id. at 130–31. On 23 August
2017, H.H. underwent stem cell treatment in Panama. Id. at 18. Upon return to the United
States, during a 29 November 2017 visit, Dr. Marks noted H.H.’s hypertonia had improved and
characterized H.H.’s disorder as “interferonopathy with elevated neopterin clinically consistent
[with] Aicardi-Goutière[s] Syndrome or other autoimmune mediated event.” Pet’rs’ Ex. 96 at 6,
ECF No. 77-1 (Cook Children’s Medical Records, pages 1–115). During a 1 October 2018 visit,
Dr. Marks described H.H.’s condition as “presumed Aicardi-Goutière[s] syndrome.” Id. at 2.
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On 10 December 2018, Dr. Marks noted H.H.’s dystonia worsened, and on 23 January
2019, H.H.’s condition remained unchanged from his 10 December 2018 appointment. Id. at 6,
11–12. H.H.’s MRI on 23 January 2019 showed “no significant change of already existing
abnormalities” and “for Aicardi-Goutières syndrome, the severity of findings was quite mild.”
Id. at 16. Additionally, H.H.’s neopterin and tetrahydrobiopterin levels were elevated. Id. at 14.
On 22 July 2019, H.H. was admitted to the hospital for seizure-like activity. Id. at 17. On 4
September 2019, Dr. Marks saw H.H. whose condition was largely unchanged from his 23
January 2019 appointment. Id. at 58–60.
II. The Petition and Procedural History Before the Special Master
Heathe and Jenna Heller, on behalf on their minor son, H.H. filed a petition on 27 July
2015 alleging H.H.’s influenza, pneumonia, and DTaP-IVH-Hib (Pentacel) vaccinations caused
or significantly aggravated H.H.’s neurological disorder. See Pet. Petitioners filed all relevant
medical records, affidavits, and expert reports from treating physicians Dr. Leslie Hollis and
Dr. Warren Marks, see ECF Nos. 19, 14, and 16, and the record was complete on 9 November
2015. See Statement of Completion, ECF No. 17. The government filed its Rule 4(c) Report
alleging the case was not appropriate for compensation and should be dismissed on 1 February
2016. See Resp’t’s Rule 4(c) Rep., ECF No. 21. Petitioners filed additional affidavits and a
supplemental expert report from Dr. Hollis on 21 March 2016. Notice of Filing, ECF No. 28
(Updated Table of Contents and Exhibit List). After a status conference with Special Master
Hasting, petitioners renumbered and refiled all previously submitted medical records, affidavits,
and expert reports. Notice of Filing, ECF No. 40 (Exhibits 48–53); Notice of Filing, ECF No.
41 (Exhibits 54–56); Notice of Filing, ECF No. 42 (Exhibits 57–63); Notice of Filing, ECF No.
43 (Exhibits 64–69); Notice of Filing, ECF No. 44 (Exhibits 70–73); Notice of Filing, ECF No.
45 (Exhibits 74–83); Notice of Filing, ECF No. 46 (Exhibits 84–93). The government filed an
expert report from Dr. Kristin Barañano with supporting medical literature on 14 December
2016. Barañano Expert Rep., ECF No. 52. Petitioners filed a supplemental expert report from
Dr. Warren Marks on 25 August 2017. Marks Expert Rep., ECF No. 54.
On 5 December 2017, the case was reassigned to Special Master Oler. Notice of
Reassignment, ECF No. 59. Petitioners filed additional medical records on 6 March 2018.
Medical Records. The government filed a supplement expert report from Dr. Barañano and an
expert report from Dr. Stephen McGeady with supporting medical literature. Supplemental
Barañano Expert Rep., ECF No. 67; First McGeady Rep. ECF No. 70; Medical Literature, ECF
No. 71. The parties filed their pre-hearing submissions on 31 December 2019 and pre-hearing
briefs along with additional medical literature on 8 January 2020. Resp’t’s Prehr’g
Submissions, ECF No. 75; Pet’rs’ Prehr’g Submissions, ECF No. 76; Pet’rs’ Prehr’g
Submissions, ECF No. 78; Pet’rs’ Prehr’g Submissions, ECF No. 79; Resp’t’s Prehr’g
Submissions, ECF No. 80; Medical Literature, ECF No. 81.
Special Master Oler held an entitlement hearing on 22 January 2020. See Entitlement
Hr’g Tr., ECF No. 88. At the conclusion of the hearing, Special Master Oler requested the
parties file several documents. See Scheduling Order of 29 January 2020, ECF No. 86. The
Special Master also “informed . . . petitioners’ counsel, that the record, as it currently stood, did
not enable [p]etitioners to meet their burden” and “suggested . . . [p]etitioners retain[] an
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additional expert neurologist.” SM Dec. at 4 n.7. Petitioners retained Dr. Lawrence Steinman
and filed the report from Dr. Steinman on 24 July 2020. See Pet’rs’ Status Rep. of 14 April
2020 at 1, ECF No. 92; Steinman Rep., ECF No. 101. The government filed another expert
report by Dr. McGeady on 1 December 2020. Second McGeady Rep., ECF No. 104. Dr.
Steinman’s reply was filed on 12 February 2021. Steinman Reply, ECF No. 108.
Petitioners filed a post-hearing brief on 15 May 2021. Pet’rs’ Posthr’g Br., ECF No.
113. The government responded on 8 July 2021, and petitioners replied on 15 July 2021.
Resp’t Posthr’g Br., ECF No. 116; Pet’rs’ Resp. to Posthr’g Br., ECF No. 118. The parties
indicated the record was complete on 9 August 2021. See JSR at 1, ECF No. 119. The Special
Master dismissed the petition on 14 April 2022. SM Dec. at 74.
In her decision on entitlement, the Special Master summarized the procedural history of
the case, the medical records of H.H., the affidavits and testimony of the fact witnesses, and the
qualifications, reports, and testimony of the parties’ experts. Id. at 1–45. The Special Master
then explained the applicable law for an off-table injury (one not included in the Vaccine Injury
Table under the Vaccine Act § 11(c)(1)(C)(ii)), including each prong of the three-part Althen
analysis used for direct causation, and each prong of the six-part Loving analysis, used for
significant aggravation claims, and the relevant standards for assessing evidence. Id. at 45–50.
The Special Master began the analysis section of her decision by making the preliminary
determination “H.H. has Aicardi-Goutières syndrome or a [s]imilar [t]ype I [i]nterferonopathy
due to a [c]ongenital [a]bnormality in an [u]nidentified [g]ene.” Id. at 50. In determining this
diagnosis, the Special Master reviewed several factors: (1) clinical presentation; (2) elevated
liver enzymes; (3) elevated interferon alpha/neopterin levels; (4) genetic mutation; (5)
calcifications; (6) basal ganglia damage; (7) normalization of neopterin levels; (8) onset of AGS
after 12 months; and (9) neurological stabilization and improvement. See id. at 50–60.
The Special Master credited the many treating physicians who found “H.H[.]’s clinical
presentation was suggestive of or consistent with AGS.” Id. at 52–53 (“Dr.
Aalbers . . . noted . . . H.H[.]’s [symptoms] . . . were all consistent with AGS.”) (“Dr. Heather
Crawford . . . . noted . . . H.H. presented with developmental regression and developed
progressive dystonia that is characteristic of [AGS].”) (“Dr. Vanderver indicated an intent to
collaborate with Dr. Crow to facilitate genetic resolution of suspected heritable
interferonopathy.”). The Special Master also relied on the opinion of Dr. McGeady, the
government’s expert, who opined H.H. had “evidence of leukodystrophy and thinning of the
corpus callosum, which are described in AGS.” SM Dec. at 52 (citing First McGeady Rep. at
4).
The Special Master highlighted the Rice paper, a 2007 study of 123 patients with a
confirmed AGS gene mutation, as supporting Dr. McGeady’s opinion of liver enzymes favoring
a diagnosis of AGS, and accordingly found H.H.’s elevated liver enzymes supported a
diagnosis of AGS. See id. at 53. Additionally, the Special Master found H.H.’s elevated levels
of neopterin and interferon alpha were diagnostic for AGS. Id. at 55 (“There was no
explanation for H.H.’s elevated neopterin and interferon alpha levels other than AGS.”). The
Special Master relied on treating physicians, medical literature, and expert testimony to make
the finding. Id. at 52–55.
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The Special Master stated “[t]he fact . . . H.H. does not have a gene currently identified
with AGS is [p]etitioners’ strongest argument that he does not have the disease.” Id. at 55. The
Special Master also acknowledged “five percent of AGS cases are associated with an
unidentified genetic mutation.” Id. (citing Barañano Rep. at 1). The Special Master did not
believe the lack of a genetic mutation or “‘major characteristics’ that have been observed in
other patients with AGS” excluded an AGS diagnosis. SM Dec. at 55. Relying on the 2015
Crow & Manel study, which discusses the molecular and cellular basis of interferonopathies,
their categorization, future treatment strategies, and the insights they provide into normal
physiology, the Special Master reasoned “‘the range of phenotypes associated with mutations’
or AGS genes ‘is much broader than previously realized’ [and] patients ‘frequently lack one or
more, sometimes even all, of the original diagnostic criteria.’” Id. (citing Crow & Manel,
Aicardi-Goutières syndrome and the type I interferonopathies, 15 NATURE REVIEWS
IMMUNOLOGY 429, 429 (2015), ECF No. 70-1 [hereinafter Crow & Manel].
Petitioners argued “H.H. does not exhibit four other ‘major characteristics’ so the
Special Master addresses those characteristics in turn. Id. H.H. did not have calcifications, but
the Special Master, replying on Dr. Barañano and Dr. McGeady’s testimonies, determined
calcifications were not required for a AGS diagnosis. Id. at 56. Considering damage to the
basal ganglia, a group of subcortical nuclei responsible primarily for motor control, the Special
Master determined “basal ganglia damage [was not] a major characteristic of AGS.” Id. at 57.
The Special Master reasoned Crow & Manel did not list basal ganglia damage as a major
characteristic. Id. at 56. The government’s expert, Dr. Barañano, testified basal ganglia
damage may be seen in AGS cases with an adenosine deaminase acting on ribonucleic acid
(“ADAR”) mutation, but it is not universally seen in all AGS cases. SM Dec. at 57.
Accordingly, the Special Master found basal ganglia damage to not be a major characteristic of
AGS and the lack of basal ganglia damage did not eliminate an AGS diagnosis. Id.
Petitioners asserted the normalization of neopterin levels is characteristic of AGS; the
Special Master disagreed. Id. at 58. The Special Master found the “medical literature . . . does
not provide compelling support for the point that it is characteristic for AGS patients to
experience normalization in neopterin level.” Id. at 57. The Special Master points out
petitioners’ expert, Dr. Marks, initially favored vaccine causation over AGS because of the
normalization in neopterin levels but reversed his position when the levels elevated again. 2 Id.
The Special Master determined the fact “H.H. developed symptoms consistent with
AGS at 15 months . . . does not provide persuasive evidence that H.H. does not have AGS, as
cases of later onset are reported in the medical literature.” Id. at 58. Various medical studies
support the notion “there is variability in AGS presentation which includes onset after the first
year of life.” SM Dec. at 58. Further, Drs. McGeady and Barañano also testified of the
variability of onset. See id.
In their post-hearing brief, H.H.’s treating physician, Dr. Marks, asserted neurological
improvement and stabilization supported a non-AGS diagnosis. Id. at 59. The Special Master
disagreed and found the medical literature supported the opinions of the government’s experts,
Drs. McGeady and Barañano, who opined “AGS is not necessarily a ‘relentlessly progressive
2
At oral argument, petitioners asserted Dr. Marks still believes H.H.’s injury is vaccine-caused. Tr. at 24:2–3.
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neurogenerative disorder’” and can have a “‘period of stabilization.’” Id. (quoting Entitlement
Hr’g Tr. at 270:8, 10–11). The Special Master found the stabilization of H.H.’s condition
supported a diagnosis of AGS. Id. at 71.
Following the diagnosis of an AGS or AGS-like disorder, the Special Master
determined the injury manifested around the time of the 17 October 2013 vaccination and
before the 23 October 2013 vaccination. Id. at 60. The Special Master found there was not
preponderant evidence to support an onset in September of 2013 because there was not
sufficient evidence to draw a conclusion, and “none of the experts explained why or how H.H.
would begin to demonstrate signs of his genetic disorder and then improve.” SM Dec. at 60.
While the Special Master did not find evidence to support onset in September of 2013, the
Special Master did find evidence for onset of symptoms after the administration of the influenza
and pneumonia vaccines but before the Pentacel vaccination. Id. at 62. The Special Master
relied on contemporaneous medical records from 11 November 2013, which indicated H.H.’s
“development ha[d] regressed in the last month,” placing the start of regression prior to the
vaccinations. Id. at 61. The Special Master considered the testimony of several fact witnesses
who also testified on H.H.’s right cord tightness, foot dragging, and falling prior to the 23
October 2013 Pentacel vaccination. Id. at 61–63.
After determining a diagnosis and narrowing the issue to whether the Pentacel vaccine
significantly aggravated H.H.’s condition, the Special Master began the six-part Loving
analysis, used to determine if a vaccine significantly aggravated H.H.’s injury. Id. at 63. For
Loving prongs one and two, which look at the condition prior to and following the
administration of a vaccination, the Special Master concisely described H.H.’s condition before
and after the 23 October 2013 vaccination. Id. In prong three of Loving, which compares the
conditions before and after the administration of a vaccination, the Special Master found the
deterioration in H.H. was “consistent with the Vaccine Act’s definition of significant
aggravation resulting in markedly greater disability, pain, or illness accompanied by substantial
deterioration of health.” Id. The Special Master then turned to the question of whether the
significant aggravation of H.H.’s condition was vaccine-related. SM Dec. at 63.
For Loving prong four, which requires a reputable medical explanation demonstrating
the vaccine received can cause the type of injury alleged, the Special Master concluded
petitioners did not establish a reliable and reputable theory. Id. at 67–68. The Special Master
analyzed petitioners’ expert Dr. Steinman’s proposed medical theory who opined the “Pentacel
vaccine activated H.H.’s immune system resulting in the production of type I and II interferons,
which led to the worsening of his neuroinflammation.” Id. at 65. The Special Master then
reviewed the medical literature used to support Dr. Steinman’s theory. Id. The literature
supported the notion “vaccines may activate the inflammasome,” but the Special Master found
“Dr. Steinman ha[d] not presented a link between such activation and the development of AGS
or a similar type I interferonopathy.” Id. at 66. Further, the Special Master credited the
government’s expert, Dr. McGeady, and reasoned petitioners’ theory did not explain how the
vaccinations caused the “massively exaggerated” levels of interferon alpha or explain how the
levels remained elevated for years after vaccination. Id. (internal quotations omitted).
Regarding Loving prong five, which requires a logical sequence of cause and effect
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between the administration of a vaccination and the significant aggravation of a condition, the
Special Master found petitioners neither provided evidence demonstrating H.H. experienced a
vaccine-associated significant aggravation of his interferonopathy nor furnished support for the
theory vaccines H.H. received affected his condition. SM Dec. at 68. First, the Special Master
determined petitioners did not present evidence of direct causation because physical signs
appeared prior to or at the same time as the 17 October vaccinations. Id. Next, the Special
Master considered the medical records and determined the medical records supported finding
the vaccine did not cause or significantly aggravate H.H.’s condition. Id. Specifically, the
Special Master points to the lack of a local reaction at the time of vaccination and the presence
of elevated transaminase levels. Id. at 68–69. The Special Master then evaluated whether the
opinions of the treating physicians, Drs. Hollis and Marks, supported a logical sequence. Id. at
69. While the treating physicians opined H.H.’s injury was vaccine caused or aggravated, the
Special Master discredited the opinions because neither expert was able to “articulate a
causation theory.” Id. at 69–72.
Finally, the Special Master considered Loving prong six, which requires the
establishment of a proximate temporal relationship between the significant aggravation of a
condition and the received vaccinations, and found petitioners did not offer “‘preponderant
proof that the onset of symptoms occurred within a timeframe which, given the medical
understanding of the disorder’s etiology . . . is medically acceptable to infer causation.’” SM
Dec. at 72 (quoting de Bazan v. Sec’y of Health & Hum. Servs., 539 F.3d 1347, 1352 (Fed. Cir.
2008)). The Special Master disvalued Dr. Steinman’s report finding H.H.’s disease course
began three weeks after his receipt of the Pentacel vaccine because Dr. Steinman did not think
there were real signs of H.H.’s interferonopathy prior to the vaccinations. Id. at 72. Further,
the Special Master analyzed each piece of medical literature Dr. Steinman used to establish an
onset time and discredited them. Id. at 73. Regarding the Schonberger, Bennetto, and Scolding
articles, research studies used to support an injury onset of three weeks, the Special Master
found the evidence unpersuasive because the articles dealt with different conditions with
different underlying mechanisms than those presented by petitioners. Id. at 73–74.
Accordingly, the Special Master found petitioners did not preponderantly establish a three-week
onset as a medically acceptable onset interval. Id. at 74.
In conclusion, the Special Master found petitioners could not establish causation under
any avenue. As such, the Special Master dismissed the petition. Id. On 16 May 2022,
petitioners moved for review of the Special Master’s decision dismissing the petition. Mot. for
Review. The government filed its brief on 15 June 2022. Resp’t’s Resp., ECF No. 127. The
Court now reviews the Special Master’s decision.
III. Petitioners’ Motion for Review and the Government’s Arguments
On 16 May 2022, petitioners filed a motion for review of the Special Master’s decision
denying entitlement with an accompanying memorandum of law. See Mot. for Review; Mot. for
Review Mem. Petitioners allege the Special Master erred in three ways: the Special Master (1)
“improperly diagnos[ed p]etitioner with AGS or another genetically caused [t]ype [sic] I
interferonopathy”; (2) “fail[ed] to recognize [p]etitioners’ expert medically sound theory of
causation of injury”; and (3) “improperly increased the burden of proof . . . for establishing the
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logical sequence . . . and establishment of a temporal relationship . . . and devalued the expert
opinion of [p]etitioners’ [sic] expert.” Id. at 1, 17–18. The Court will divide petitioners’ third
objection into Loving prongs five and six, as the government did in its response. See Resp’t’s
Resp. at 10–12.
A. The Special Master’s Diagnosis of AGS
Petitioners argue “the [d]ecision denying entitlement . . . rests largely with the [S]pecial
[M]aster diagnosing . . . H.H. with AGS or some other unknown genetic Type I
interferonopathy.” Mot. for Review Mem. at 13. While petitioners do not “contest that H.H.’s
injury is ‘AGS-like,’” petitioners assert the Special Master erred by “improperly characteriz[ing]
the meaning of ‘AGS-like’ to suggest that [p]etitioners’ expert, Dr. Steinman was agreeing that
‘AGS-like’ meant that H.H. had a genetic interferonopathy” rather than a type I interferonopathy
caused by the October 2013 vaccinations. Id. at 14.
Petitioners assert their “almost impossib[le] H.H. has AGS based off of the known
medical statistics of the major characteristics of AGS.” Id. Petitioners argue Dr. Steinman
testified “there is no evidence or the probability is extremely low that H.H. has AGS or some
unk[n]own gen[e]tic AGS[-]like disease based off the medical records and based off the leading
experts in the world regarding AGS not having been able to diagnose him with the disease.” Id.
Petitioners argue the Special Master even recognized the low probability of H.H. having AGS or
some unknown genetic AGS-like disorder. See id. at 14–15 (“[I]n 5% of AGS cases, there are no
recognized genetic mutation, which would include H.H. Additionally, in 18% of AGS cases,
there’s normal development until symptom onset, which would include [p]etitioner. Also, in
8.6% of the AGS cases, development happens after 12 months, again, which includes
[p]etitioner, and then in 25% of cases ‘there is normalization of neopterin levels, and then in
some other percent of cases, there are no calcifications.”). Petitioners indicate the Special
Master acknowledged “‘a fair number of absences’ that are not consistent with an AGS
diagnosis” stating, “when you take all of those numbers and look at them together—and I’m not
saying I’m making a decision based on the numbers[, b]ut when you take all those numbers and
look at them together, this really seems like well beyond one in a million . . . . it seems like an
exceedingly rare instance.” Id. at 15 (citing Entitlement Hr’g Tr. 290:9–291:15). Petitioners
assert “despite the absolutely near impossibility” the Special Master “went against the great
weight of evidence presented . . . and diagnosed [p]etitioner with ‘more likely than not’ AGS or a
similar generic disorder, with a complete unknown etiology.” Id. Petitioners further assert the
government did not provide any medical evidence alleging the vaccinations “could not have
caused his injury and only provided evidence that they are not aware of any [medical evidence]
at this time, and therefore default to a differential diagnosis.” Id.
The government disagrees, stating the Special Master “thoroughly reviewed the
evidence” when the Special Master “considered [H.H.’s] clinical presentation, elevated liver
enzymes, elevated interferon alpha/neopterin levels, and more, found persuasive the opinions of
Drs. Barañano and McGeady, considered the notations in the medical records, and weighed the
medical literature” to determine that “H.H[.]’s condition was consistent with a diagnosis of AGS
or an AGS-like genetic condition.” Resp’t’s Resp. at 13 (cleaned up). The government argues
the “Special Master’s conclusion . . . is well-supported by both expert opinion and the medical
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records[.]” Id. (“In sum, she thoroughly reviewed the evidence and explained her reasoning, and
her findings should not be disturbed.”). The government indicates the “Special Master discussed
at length the qualification of each expert witness, the testimony of each, and the field of medical
literature submitted by both parties,” and, therefore, the Special Master’s “factual findings
should be given the discretion they are entitled to.” Id. at 13–14. The government further argues
the diagnosis, even if erroneous, would not be fatal to the decision because petitioners “failed to
meet their burden under any of the three Althen prongs [or Loving prongs 5 and 6],” which
establishes causation in fact when the petitioner proves all three Althen prongs, and “failure to
meet their burden under even one is dispositive and fatal to their case.” Id. at 14.
B. Loving Prong Four/Althen Prong One: A Medical Theory Causally
Connecting the Vaccination and the Injury
Petitioners argue in their second objection the Special Master “fail[ed] to recognize
[p]etitioners’ expert medically sound theory of causation of injury.” Mot. for Review Mem. at 1.
Citing Althen, petitioners argue circumstantial evidence can be used to meet the preponderance
standard in a “field bereft of complete and direct proof of how vaccines affect the human body.”
Id. at 16 (quoting Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274, 1280 (Fed. Cir.
2005)). Petitioners assert they “provided a medical theory, albeit in an area bereft of medical
literature and knowledge of the mechanism of injury that [p]etitioner[s’] interferonopathy was
caused or substantially aggravated by the vaccines H.H. received, and that H.H. does not have
AGS or a similar unknown genetic injury.” Id. Petitioners argue “Dr. Steinman, produced
med[ical] literature that supports his theory that [v]accinations can cause the production of
interferon,” and, in turn, “experts agree that overproduction or an excessive amount of
interferons can cause the type of injury seen in [H.H.].” Id. Petitioners continue, Dr. Steinman
“offered testimony that interferon response was absent or deficient in H.H. and as a result his
immune system continuously produced type I interfe[ron], which resulted in the disease.” Id. at
17.
Petitioners argue the Special Master’s decision improperly required petitioners to
“produce either testimony or medical literature to state that in this particular case, the vaccines
did not cause [H.H.] to overproduce interferons.” Id. Additionally, petitioners argue they had to
“prove that the vaccinations of October 2013 could cause [interferon] production and that the
[interferons] produced to a level that caused grave injury[—]the injury being one that resembles
a genetic disease . . . but only a scintilla of evidence suggests that H.H.’s injury is caused by
genetic mutation.” Mot. for Review Mem. at 17. Petitioners assert the government’s expert did
not “provide any evidence that the vaccinations could not have caused his injury” but has “only
provided testimony from non-treating physicians that opine[d] they are not aware of any medical
literature or cases where a vaccination caused an “AGS-[l]ike” interferonopathy.” Id. at 15–16.
Under Althen, petitioners argue, the issue of “whether H.H. has AGS and if a vaccine could
cause it” is a “close call” and should be resolved in favor of petitioners. Id. at 1, 16 (citing
Althen, 418 F.3d at 1280).
The government argues petitioners “failed to establish a reliable and reputable theory” or
“reliable evidence in support of the[] theor[y].” Resp’t’s Resp. at 6, 8. The government asserts
Althen prong one requires “a medical theory be ‘persuasive’—that is, a specific to petitioners’
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case and supported by a ‘reputable’ (i.e., reliable) scientific or medical explanation.” Id. at 5
(citing Moberly v. Health & Hum. Servs., 592 F.3d 1315, 1322 (Fed. Cir. 2010)). See Boatmon
v. Sec’y of Health & Hum. Servs., 941 F.3d 1351, 1360 (Fed. Cir. 2019) (rejecting “likely
caused,” “plausible,” or “possible” causal theories). The government asserts it is in the Special
Master’s purview to reject—as the Special Master did— “an expert’s conclusion ‘connected to
existing data only by the ipse dixit of the expert,’ especially if ‘there is simply too great an
analytical gap between the data and the opinion proffered.’” Id. at 8 (quoting Snyder v. Sec’y of
Health & Hum. Servs., 88 Fed. Cl. 706, 743 (2009)). Additionally, the government contends the
Special Master “carefully considered the qualifications, written reports, and testimony of all the
experts, as well as the literature, and appropriately determined petitioners’ theory was not
supported by a reputable scientific explanation.” Id. Specifically, the government agrees with
the Special Master’s conclusion regarding “one of the articles upon which Dr. Steinman heavily
relied” to show vaccinations may trigger a interferonopathy “does not provide persuasive
evidence in support of [p]etitioners’ theory in this case.” Id. at 8. The government further
asserts petitioners “provided a wholly speculative theory that was not supported by the scientific
research,” and even if petitioners “had provided sufficient evidence to establish that Dr.
Steinman’s theory was possible, that would not have been sufficient to meet their burden.” Id. at
10. Additionally, the government argues petitioners’ characterization of causation as a “close
call” indicates the legal insufficiency and lack of reliable and reputable evidence to support the
causation. Id. at 9–10.
C. Loving Prong Five/Althen Prong Two: A Logical Sequence of Cause and
Effect Showing the Vaccination was the Reason for the Injury
Petitioners’ third objection, in part, relates to the Special Master’s analysis of the logical
sequence of cause and effect between the administration of the vaccination and the manifestation
of the injury. Mot. for Review Mem. at 17 (“The [d]ecision improperly increased the burden of
proof past the preponderance of the evidence standard for establishing a logical sequence of
cause and effect.”). Petitioners allege the Special Master “devalued . . . [the p]etitioners’ expert”
who “provided evidence sufficient to satisfy [p]rongs 5 and 6 of Loving when discussing whether
the Pentacel vaccination significantly aggravated H.H.’s injury, which would also satisfy
Althen.” Id. at 19. Citing the Federal Circuit, petitioners further assert “the question of whether
an expert’s theory has been subjected to peer review and publication is not determinative of an
expert’s reliability” nor should an expert’s opinions on causation be “held to the standard of
scientific certainty” or “viewed through the lens of the laboratorian.” Id. at 18 (first quoting
Boatmon, 941 F.3d at 1359; then quoting Andreu ex rel. Andreu v. Sec’y of Health & Hum.
Servs., 569 F.3d 1367, 1380 (Fed. Cir. 2009)). By devaluing expert opinion, petitioners argue
the Special Master increased the burden of proof for petitioners. Id. at 18.
The government maintains, as the Special Master concluded, “H.H[.]’s deterioration
. . . close-in-time to his vaccination” and the mere fact “no other explanation exists” is
insufficient to show the vaccines caused a significant aggravation of H.H.’s condition. Resp’t’s
Resp. at 11. The government, citing Moberly, argues petitioners did not meet the burden of
showing actual causation because a proximate temporal relationship between vaccine and injury
is insufficient. Id. at 11 (citing Moberly ex rel. Moberly v. Sec’y of Health & Hum. Servs., 592
F.3d 1315, 1323 (Fed. Cir. 2010) (holding “mere showing of a proximate temporal relationship
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between vaccine and injury, nor a simplistic elimination of other potential causes of injury
suffices”)).
D. Loving Prong Six/Althen Prong Three: A Showing of a Proximate Temporal
Relationship Between Vaccination and the Injury
Petitioners assert in the second half of their third objection the Special Master “increased
the burden of proof . . . to prove the theory that H.H. was a healthy child prior to his October
2013 vaccinations, and with three weeks of those vaccinations, he was a severely and
permanently injured child.” Mot. to Review Mem. at 18. Petitioners argue they met their burden
of proof because “‘the proximate temporal relationship prong requires preponderant proof that
the onset of symptoms occurred with a timeframe for which, given the medical understanding of
the disorder’s etiology, it is medically acceptable to infer causation-in-fact.’” Id. (quoting de
Bazan v. Sec’y of Health & Hum. Servs., 529 F.3d 1347, 1352 (Fed. Cir. 2008)). Petitioners
argue Dr. Steinman, petitioners’ expert, “concisely and with supporting medical literature
provided evidence sufficient to satisfy prong[s] 5 and 6 of Loving . . . which would also satisfy
Althen.” Id. Petitioners argue the Special Master erroneously dismissed its expert’s testimony
showing temporal causation. Id.The government asserts the Special Master was correct in finding petitioners unable to
establish a proximate temporal relationship regarding the significant aggravation claim. Resp’t’s
Resp. at 12, 12 n.4. The government argues—and the Special Master found—petitioner did not
establish a medically acceptable timeline from which to infer causation. Id. The temporal
relationship analysis “necessarily intersects with the prong one analysis (providing a reliable
medical theory causally connecting the resulting condition to the received vaccinations),” and
therefore, the government argues, petitioners could not have met their burden because they did
not present a reliable medical theory related to the “onset or worsening of the disease.” Id. at 11.
The government further argues the Special Master’s decision was “well-support[ed] by
evidence” and well-reasoned as the Special Master “carefully considered the qualifications,
written reports, and testimony of all the experts, as well as the literature.” Id. at 12, 8.
Specifically, the government agrees with the Special Master’s finding an article related to the
onset of GBS after swine flu vaccination was used in support of petitioners’ timing argument,
unpersuasive because the vaccination, injury, and theory of causation were not analogous. Id. at
12, 12 n.5.
IV. Legal Standards
A. The Court’s Standard of Review of a Special Master’s Decision
The Vaccine Act provides this Court jurisdiction to review a special master’s decision
upon timely motion of either party. See 42 U.S.C. § 300aa-12I(1)–(2) (2018). In reviewing the
record of the proceedings before the special master, the Court may: (1) “uphold the findings of
fact and conclusions of law of the special master and sustain the special master’s decision”; (2)
“set aside any findings of fact or conclusion of law of the special master found to be arbitrary,
capricious, an abuse of discretion, or otherwise not in accordance with law and issue its own
findings of fact and conclusions of law”; or (3) “remand the petition to the special master for
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further action in accordance with the court’s direction.” Id. at § 300aa-12(e)(2). “Fact findings
are reviewed . . . under the arbitrary and capricious standard; legal questions under the ‘not in
accordance with law’ standard; and discretionary rulings under the abuse of discretion standard.”
Saunders v. Sec’y of Health & Hum. Servs., 25 F.3d 1031, 1033 (Fed. Cir. 1994) (quoting Munn
v. Sec’y of Health & Hum. Servs., 970 F.2d 863, 870 n.10 (Fed. Cir. 1992)).
It is not the Court’s role “to reweigh the factual evidence, or to assess whether the special
master correctly evaluated the evidence.” Lampe v. Sec’y of Health & Hum. Servs., 219 F.3d
1357, 1360 (Fed. Cir. 2000) (quoting Munn, 970 F.2d at 871). The Court also does “not examine
the probative value of the evidence or the credibility of the witnesses.” Id. These are all matters
within the purview of the fact finder.” Id. (quoting Munn, 970 F.2d at 871). “Reversal is
appropriate only when the special master’s decision is arbitrary, capricious, an abuse of
discretion, or not in accordance with the law.” Snyder v. Sec’y of Health & Hum. Servs., 88 Fed.
Cl. 706, 718 (2009). The arbitrary and capricious standard “is a highly deferential standard of
review[:] [i]f the special master has considered the relevant evidence of record, drawn plausible
inferences and articulated a rational basis for the decision, reversible error will be extremely
difficult to demonstrate.” Hines ex rel. Sevier v. Sec’y of Health & Hum. Servs., 940 F.2d 1518,
1528 (Fed. Cir. 1991).
B. The Standard of Causation in Vaccine Cases
“A petitioner seeking compensation under the Vaccine Act must prove by a
preponderance of the evidence that the injury or death at issue was caused by a vaccine.”
Broekelschen v. Sec’y of Health & Hum. Servs., 618 F.3d 1339, 1341 (Fed. Cir. 2010) (citing 42
U.S.C. §§ 300aa-11(c)(1), 300aa-13(a)(1)). “A petitioner can show causation under the Vaccine
Act in one of two ways”: (1) “by showing that she sustained an injury in association with a
vaccine listed in the Vaccine Injury Table[,] . . . [i]n such a case, causation is presumed”; or (2)
“if the complained-of injury is not listed in the Vaccine Injury Table . . . the petitioner may seek
compensation by proving causation in fact.” Id. at 1341–42 (internal citations omitted). Vaccine
cases employ a burden shifting standard: “[o]nce the petitioner has demonstrated causation, she
is entitled to compensation unless the government can show by a preponderance of the evidence
that the injury is due to factors unrelated to the vaccine.” Id. at 1342 (citing Doe v. Sec’y of
Health & Hum. Servs., 601 F.3d 1349, 1351 (Fed. Cir. 2010)).
“For off-table claims (one not included in the Vaccine Injury Table under the Vaccine Act
§ 11(c)(1)(C)(ii)) that an injury was either ‘sustained, or [] significantly aggravated,’ a petitioner
must show the vaccine ‘caused’ the injury or aggravation.” W.C. v. Sec’y of Health & Hum. Servs.,
704 F.3d 1352, 1357 (Fed. Cir. 2013) (citing 42 U.S.C. § 300aa-11(c)(1)(C)(ii)). “When a
petitioner has suffered an off-[t]able injury . . . [the Federal Circuit] has established the following
test for showing causation in fact under the Vaccine Act:”
[The petitioner’s] burden is to show by preponderant evidence that the vaccination
brought about her injury by providing: (1) a medical theory causally connecting
the vaccination and the injury; (2) a logical sequence of cause and effect showing
that the vaccination was the reason for the injury; and (3) a showing of a proximate
temporal relationship between vaccination and injury.
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Broekelschen, 618 F.3d at 1345 (quoting Althen, 418 F.3d at 1278). “A petitioner must prove by
preponderant evidence that the vaccination caused significant aggravation by showing:”
(1) the person’s condition prior to administration of the vaccine, (2) the person’s
current condition (or the condition following the vaccination if that is also
pertinent), (3) whether the person’s current condition constitutes a “significant
aggravation” of the person’s condition prior to vaccination, (4) a medical theory
causally connecting such a significantly worsened condition to the vaccination, (5)
a logical sequence of cause and effect showing that the vaccination was the reason
for the significant aggravation, and (6) . . . a proximate temporal relationship
between the vaccination and the significant aggravation.
W.C., 704 F.3d at 1357 (Fed. Cir. 2013) (citing Loving ex rel. Loving v. Sec’y of Health & Hum.
Servs., 86 Fed. Cl. 135, 144 (2005)). The Federal Circuit in W.C. espoused “[t]he Loving test
combines the first three Whitecotton factors, which establish significant aggravation, with the
Althen factors, which establish causation.” Id. Accordingly, the standards for assessing Althen
prongs 1–3 also apply to Loving prongs 4–6. Id.Under the first prong of Althen, “[a] petitioner must provide a ‘reputable medical or
scientific explanation’ for its theory.” Boatmon, 941 F.3d at 1359 (quoting Moberly, 592 F.3d at
1322). “While it does not require medical or scientific certainty, [the explanation] must still be
‘sound and reliable.’” Id. (quoting Knudsen ex rel. Knudsen v. Sec’y of Health & Hum. Servs.,
35 F.3d 543, 548–49 (Fed. Cir. 1994)). Petitioners “need not produce medical literature or
epidemiological evidence to establish causation under the Vaccine Act.” Andreu ex rel. Andreu
v. Sec’y of Health & Hum. Servs., 569 F.3d 1367, 1379 (Fed. Cir. 2009). Where such evidence is
introduced, it must not be viewed “through the lens of the laboratorian, but instead from the
vantage point of the Vaccine Act’s preponderant evidence standard” Id. at 1380. For satisfying
the second Althen prong, “medical records and medical opinion testimony are favored in vaccine
cases, as treating physicians are likely to be in the best position to determine whether ‘a logical
sequence of cause and effect show[s] that the vaccination was the reason for the injury.’”
Capizzano v. Sec’y of Health & Hum. Servs., 440 F.3d 1317, 1326 (Fed. Cir. 2006) (quoting
Althen, 418 F.3d at 1280). Lastly, “the proximate temporal relationship prong requires
preponderant proof that the onset of symptoms occurred within a timeframe for which, given the
medical understanding of the disorder’s etiology, it is medically acceptable to infer causation-in-
fact.” de Bazan v. Sec’y of Health & Hum. Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008).
V. Review of the Special Master’s Decision on Entitlement
Petitioners alleged H.H.’s injuries were caused or significantly aggravated by the
influenza, pneumonia, and Pentacel vaccines, administered on 17 October 2013 and 23 October
2013, respectively. See Pet. at 1. The Special Master reviewed the record for each of the three
vaccines as the cause or significant aggravation of H.H.’s injury. SM Dec. at 63 (“I am unable to
make a specific finding as to whether H.H. began to develop signs of his type I interferonopathy
before or after the flu and pneumonia vaccines, I have not analyzed whether these vaccines either
caused or significantly aggravated H.H.’s condition.”). In their memorandum regarding their
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motion for review, petitioners alleged the Special Master erred in determining whether any of the
three vaccines caused or significantly aggravated H.H.’s injury. Mot. for Review Mem. at 11, 18
(“[T]ype I interferonopathy [was] caused by the vaccination[-]triggering event in October
2013.” (emphasis added)) (asserting the Special Master erred in applying Loving prongs 4, 5 & 6
for the significant aggravation analysis). Accordingly, the Court reviews the Special Master’s
decision to determine whether the Special Master erred in finding the influenza, pneumonia, and
Pentacel vaccines did not cause or significantly aggravate H.H.’s type I interferonopathy.
A. The Special Master’s Consideration of the Influenza and Pneumonia
Vaccinations
As part of the Special Master’s decision, the Special Master considered whether the
influenza and pneumonia vaccines caused or significantly aggravated H.H.’s injury. SM Dec. at
63. The Special Master stated, “I have not analyzed whether [the influenza and pneumonia]
vaccines either caused or significantly aggravated H.H.’s condition because Dr. Steinman only
offered an opinion with respect to the Pentacel vaccine.” Id. The Special Master did not analyze
causation–in–fact for the influenza and pneumonia vaccinations because petitioners did not
present evidence showing causation in fact for influenza and pneumonia. Id. Petitioners did not
expressly object to this finding in their motion for review. See Mot. for Review Mem. at 1.
At oral argument, the parties disputed the scope of Dr. Steinman’s report. See Tr., ECF
No. 131. Under the Vaccine Act, petitioners seeking compensation “must prove by a
preponderance of the evidence that the injury or death was caused by a vaccine.” Broekelschen
v. Sec’y of Health & Hum. Servs., 618 F.3d 1339, 1341 (Fed. Cir. 2010) (citing 42 U.S.C. §§
300aa-11(c)(1), 300aa-13(a)(1)). At oral argument, the government posited “Dr. Steinman only
addresses the Pentacel vaccine” and argued the discussion of the Special Master’s decision
should be limited to the findings related to Pentacel. Tr. at 13:12–15. Petitioners stated Dr.
Steinman “did reference both sets of vaccinations having been causes of the injury” in generic
terms, but Dr. Steinman “focus[ed] on Pentacel” when opining on the medical theory and
causation in fact of H.H.’s injury. Id. at 37:18–21. After further questioning, petitioners
conceded their “theory is that the Pentacel significantly aggravated his interferonopathy and
caused it.” Id. at 91:12–15. Specifically, petitioners did not provide a medical theory showing
the influenza and/or pneumonia vaccines can cause interferonopathies. SM Dec. at 63 (“Dr.
Steinman only offered an opinion with respect to the Pentacel vaccine.”); Tr. at 37:18–21 (“THE
COURT: [D]oes Dr. Steinman address all three vaccines? [PETITIONERS]: He addresses
them . . . in a more general term, as the October 2013 vaccinations, including the flu vaccination
and then Pentacel . . . so he did reference both sets of vaccinations and having been causes of the
injury, but did then focus on Pentacel . . . .”), 38:1–3 (“THE COURT: [I]t’s fair to say, that Dr.
Steinman’s report focuses on Pentacel? [PETITIONERS]: It does focus on Pentacel.”). The
parties both agree petitioners’ expert, Dr. Steinman, focused on the medical theory related to the
components contained in the Pentacel vaccine. Id. at 13:12–15, 37:18–21.
Petitioners seeking compensation “must prove by a preponderance of the evidence that
the injury or death was caused by a vaccine.” Broekelschen, 618 F.3d at 1341 (citing 42 U.S.C.
§§ 300aa-11(c)(1), 300aa-13(a)(1)). The parties agree—and the Special Master found—Dr.
Steinman did not opine on the influenza and pneumonia vaccines, and therefore did not put forth
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evidence to show causation. Id. Accordingly, the Court finds the Special Master did not err in
finding the influenza and pneumonia vaccines did not cause H.H.’s injury. Id.
B. The Special Master’s Consideration of Direct Causation v. Significant
Aggravation
There are two separate avenues to recovery under the Vaccine Act: a petitioner can
allege a vaccine (1) caused a new injury; or (2) significantly aggravated an existing injury.
Loving, 86 Fed. Cl. at 143. The Federal Circuit explained “vaccine-related injury or death”
means “illness, injury, condition, [that] has to be more than just a symptom or manifestation of
an unknown injury.” 3 Lombardi v. Sec’y of Health & Hum. Servs., 656 F.3d 1343, 1352 (citing
Broekelschen, 618 F.3d at 1349). Two injuries—like a genetic injury and a vaccine-aggravated
injury—can have overlapping symptoms. See Broekelschen, 618 F.3d at 1346 (observing the
two disputed injuries, transverse myelitis and anterior spinal artery syndrome, had overlapping
symptoms).
In this case, petitioners alleged entitlement under both avenues, so the Special Master
considered whether the Pentacel vaccine caused or significantly aggravated H.H.’s injury. SM
Dec. at 63. The Special Master found “the Pentacel vaccine did not [directly] cause H.H.’s
condition” because “H.H. began to show signs of his type I interferonopathy before he received
the Pentacel vaccine,” and eliminated a direct causation analysis. Id. (citing Locane v. Sec’y of
Health & Hum. Servs., 685 F.3d 1375, 1381 (Fed. Cir. 2012)). The Special Master found “H.H.
began to develop heel cord tightness around the time he received his October 17, 2013
vaccinations, and before the received the Pentacel vaccine, and further that this heel cord
tightness constituted a physical sign of his type I interferonopathy.” Id. at 72. Accordingly, the
Special Master focused on the significant aggravation of H.H.’s injury. Id. at 63 (“My finding
. . . makes the analysis more pointed. It . . . raises the question as to whether the Pentacel
vaccine caused the significant aggravation of H.H.’s genetic condition that had already begun to
manifest.”).
The parties dispute whether petitioners allege a direct causation theory or a significant
aggravation theory on review. In their memorandum regarding their motion for review,
petitioners stated H.H.’s “interferonopathy was caused or substantially aggravated” by the
vaccinations received. Mot. for Review Mem. at 16. The government argued petitioners only
focus on a significant aggravation theory because “[p]etitioners did not raise any legal
challenges” to the Special Master’s factual finding physical signs of interferonopathy—heel cord
tightening—around October 17, 2013. Resp’t’s Resp. at 12 n.4; Tr. at 91:5–15
([PETITIONERS]: [W]e did not specifically address her fact finding in [] our motion for
review.”). By not challenging the factual finding, the government suggests petitioners’ motion
for review and memorandum regarding their motion to review “assumes that the case involves
the significant aggravation of their son’s pre-existing condition.” See Resp’t’s Resp. at 12, 12
n.4.
3
The Special Master in her decision uses “diagnosis,” “disorder,” and “condition” terminology interchangeably with
injury.
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During oral argument, both parties agreed with the Special Master in finding the onset of
symptoms were sometime between 17 October 2013 and 23 October 2013. Tr. at 90:1–19. At
the beginning of oral argument, petitioners generally maintained “the injury was caused by the
vaccination, causing a type I interferonopathy.” Id. at 8:10–22. If the injury was not caused by
vaccine, petitioners alternatively asserted, “a genetic type I interferonopathy, an unknown
genetic type I interferonopathy . . . was significantly aggravated by the vaccinations.” Id.
Regarding timing, petitioners recognized at the 13 October 2013 flu vaccinations appointment,
“there were signs that he . . . began to have overactive interferons.” Id. at 90:11-16. Petitioners
conceded the manifestation of physical signs around the 13 October 2013 vaccinations
appointment points to significant aggravation as the primary theory. Id. at 90:20–22
(“[PETITIONERS]: It is petitioners’ belief . . . [at] the October 13th flu vaccination . . . there
were signs . . . that he began to have overactive interferons . . . that puts us into the significantly
aggravated case or area of law.”). While petitioners did not “want to take the complete causation
theory off the table,” they acknowledged “Dr. Steinman just opined in his expert report, focusing
on a significant aggravation theory.” Id. at 91:2–9 (“THE COURT: [A]re petitioners still
making a complete causation theory? [PETITIONERS]: I don’t want to take the complete
causation theory off the table, but our expert witnesses relied and testified—well Dr. Steinman
just opined in his expert report, focusing on a significant aggravation theory. [E]specially with
the Special Master’s fact-finding, we did not specifically address her fact-finding in . . . our
motion for review.”). Consequently, as petitioners stated, “evidence of a slight heel cord
tightening” favors “Pentacel significantly aggravating [H.H.’s] interferonopathy” as petitioners’
primary theory. Tr. at 90:20–22, 91:10–15 (“[PETITIONERS]: There was evidence of a slight
heel cord tightening, so petitioners’ theory is that the Pentacel significantly aggravated his
interferonopathy and caused it.”).
In this case, the Special Master found “preponderant evidence that the onset of H.H.’s
condition began close-in-time to his October 17, 2013 vaccinations and before he received the
Pentacel vaccine.” SM Dec. at 63. The Special Master relied on contemporaneous medical
records from 11 November 2013, which indicated H.H.’s “development ha[d] regressed in the
last month,” placing the start of regression prior to the vaccinations. Id. at 61. The Special
Master considered the testimony of several fact witnesses who also testified about H.H.’s right
cord tightness, foot dragging, and falling prior to the 23 October 2013 Pentacel vaccine. Id. at
61–63. Given all the evidence, the Special Master found “H.H. began to show signs of his type I
interferonopathy before he received the Pentacel vaccine.” Id. at 63 (emphasis added). As
petitioners raised no allegation of error in the Special Master’s factual finding, the Court does not
review the finding for error.
Evidence of physical symptoms prior to vaccination eliminates a direct causation claim.
Locane, 685 F.3d at 1381 (“[I]f the illness was present before the vaccine was administered,
logically, the vaccine could not have caused the illness.”). The Special Master found “H.H.
began to develop heel cord tightness around the time he received his 17 October 2013
vaccinations[] and before he received the Pentacel vaccine, and . . . this heel cord tightness
constituted a physical sign of his type I interferonopathy,” which eliminates the possibility of the
vaccine directly causing H.H.’s injury. SM Dec. at 63 (citing Locane, 685 F.3d at 1381).
Petitioners’ expert Dr. Steinman could not account for the early symptoms stemming from
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H.H.’s genetic injury in his direct causation theory. 4 Tr. at 91:2–9 ([PETITONERS]: “Dr.
Steinman . . . focus[ed] on a significant aggravation theory.”). The parties do not dispute the
Special Master’s factual finding of physical symptoms manifesting prior to administration of the
Pentacel vaccine and therefore agree the finding eliminates a direct causation theory. Tr. at
90:20–22. Accordingly, the Court finds the Special Master did not err in only analyzing a
significant aggravation theory for Pentacel because the physical symptoms of H.H.’s genetic
injury appeared before his Pentacel vaccination. See Locane, 685 F.3d at 1381(stating if “the
illness was present before the vaccine was administered, logically, the vaccine could not have
caused the illness”).
VI. The Special Master’s Determination of Genetically Caused AGS or AGS-like Type I
Interferonopathy
Before Special Master Oler analyzed whether the Pentacel vaccine could have
significantly aggravated H.H.’s injury, the Special Master determined the record best supported
an AGS or AGS-like type I interferonopathy injury. SM Dec. at 50–63. Petitioners first object
to the Special Master “improperly diagnosing [H.H.] with AGS or another genetically caused
[type] [sic] I interferonopathy[.]” Mot. for Review Mem. at 1. The Court will review the
Special Master’s decision as it relates to petitioners’ theory of significant aggravation of H.H.’s
injury by the Pentacel vaccine by first determining whether the Special Master erred in her
diagnosis of AGS or AGS-like type I interferonopathy.
A. Whether the Special Master was Required to Diagnose
The Special Master’s diagnosis is central to the parties’ dispute in this case. The Special
Master “found the evidence preponderantly supports the fact that H.H. has a genetic type I
interferonopathy that is either AGS or is AGS-like.” SM Dec. at 63. Petitioners object to the
finding because it “improperly mischaracterized the meaning of ‘AGS-like’ to suggest . . . H.H.
had a genetic [t]ype I [i]nterferonopathy as opposed to the October 2013 vaccinations causing the
[t]ype I [i]nterferonopathy.” Mot. for Review Mem. at 14. The government disagrees the
Special Master erred in the diagnosis and further asserts, even if the “diagnosis was erroneous,
such error would be harmless” because petitioners “failed to meet their burden under any of the
three Althen prongs,” which is “dispositive and fatal to their case.” Resp’t’s Resp. at 14.
Before the Court can assess whether the Special Master mischaracterized the diagnosis, it
must determine whether a diagnosis was allowed. Causation frameworks are determined
4
Dr. Steinman opined on both an onset theory and a significant aggravation theory. See Steinman Rep. at 15–16.
The Special Master found Dr. Steinman’s opinion supporting an onset claim contrary to her findings of physical
signs prior to the Pentacel vaccine. SM Dec. at 72 (“[M]y determination in this case is contrary to Dr.
Steinman’s.”). Dr. Steinman did not believe “H.H. had pre-existing evidence of a neurological problem, unless the
turning of the right foot inward was the earliest manifestation of dystonia.” Steinman Rep. at 5. Dr. Steinman’s
report, however, acknowledges early physical signs but does not believe those were neurological signs. Id.
Accordingly, he does not address how an onset theory accounts for them directly. Steinman Rep. at 8 (“Based on
the records, I conclude that this is an interferonopathy with precious little evidence of any neurologic findings prior
to the immunizations in October 2013.”). In his reply, Dr. Steinman asserts “even if there was an underlying AGS
condition in play in H.H., my logic is that the immunization would have worsened neuroinflammation in H.H.”
Steinman Reply at 3.
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“relative to the injury.” Broekelschen v. Sec’y of Health & Hum. Servs., 618 F.3d 1339, 1346
(Fed. Cir. 2010). Accordingly, a special master may “first determine which injury was best
supported by the evidence presented in the record before applying the Althen test[.]” Id.(emphasis added). In this case, the Special Master relied on Broekelschen to justify diagnosing
H.H. prior to any causation analysis and found “in considering the evidence . . . . H.H., more
likely than not, has AGS or a similar genetic interferonopathy.” SM Dec. at 50, 60. In
Broekelschen, the petitioner presented symptoms characteristics of two distinct diagnoses.
Broekelschen, 618 F.3d at 1343. Each diagnosis had a predetermined cause. Id. at 1346(“Transverse myelitis is an inflammatory event caused by an immune response, whereas anterior
spinal artery syndrome is a vascular event caused by a blockage.”). The Federal Circuit
explained “nearly all of the evidence on causation was dependent on the diagnosis” and “because
the injury itself [was] in dispute, the proposed injuries differ[ed] significantly in their pathology,
and the question of causation turn[ed] on which injury [petitioner] suffered.” Id. The Federal
Circuit held “it was appropriate . . . for the special master to first determine which injury was
best supported by the evidence presented in the record before applying the Althen test so that the
special master could subsequently determine causation relative to the injury.” Id. In
Broekelschen, a causation analysis could not proceed without defining an injury, so the special
master had to define the injury. See id.In contrast, the parties in Andreu agreed the petitioner suffered from a seizure disorder
but disputed whether an initial seizure was febrile or afebrile. Andreu ex rel. Andreu v. Sec’y of
Health & Hum. Servs., 569 F.3d 1367, 1378 (Fed. Cir. 2009). The Federal Circuit suggested the
exact diagnosis or injury was not required to determine whether the vaccine caused the
petitioner’s injury because both parties agreed “whatever caused [petitioner’s] first seizure also
led to his subsequent seizure disorder.” Id. at 1381. The question of whether the seizure was
febrile or afebrile did “not change [the dispute] that the catalyst . . . was the . . . vaccine . . . [,]”
and, similarly, the dispute in this case was not whether H.H. had an interferonopathy but whether
“the October 2013 vaccinations caus[ed] the [t]ype I [i]nterferonopathy.” Id. at 1378; Mot. for
Review Mem. at 14. If the special master in Andreu had provided a diagnosis, narrowing the
petitioner’s injury to afebrile or febrile, the causation analysis would remain unchanged because
the question was still if the vaccine caused the injury. In other words, an exact diagnosis was not
needed to move forward with a causation analysis like it was in Broekelschen. See Andreu, 569
F.3d at 1378.
The preliminary question before the Court can address the diagnosis itself is whether the
Special Master’s diagnosis was permitted under Andreu. In this case, the parties do not dispute
the injury—type I interferonopathy—is an inherited genetic disorder. 5 Tr. 28:15–17 (“[THE
GOVERNMENT]: [M]y understanding is it’s an interferonopathy[.]”), 29:25
(“[PETITIONERS]: The injury is an interferonopathy.”). Instead, the parties dispute the
underlying cause of the interferonopathy and whether the vaccine aggravated the injury. Id. at
10:14–19 (“THE COURT: [I]s it fair to say that the primary dispute here is the underlying cause
of the injury, whether it was genetic or vaccine? [PETITIONERS]: The underlying
5
Type I interferonopathies are a group of “monogenic diseases in which a constitutive upregulation of type I
[interferon] production is considered directly relevant to pathogenesis.” SM Dec. at 56 (quoting Crow & Manel at
430); see also SM Dec. at 64 (“Rodero & Crow[] describe[es] ‘the grouping of Mendelian disorders associated with
an up-regulation of type I interferon signaling as a novel set of human inborn errors of immunity.’”).
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cause . . . .”). The Special Master did not need to diagnose—and the parties agree—because the
injury itself was not disputed but rather “whether the . . . vaccine [caused the injury].” See
Andreu, 569 F.3d at 1378; Tr. at 25:8–16 (“THE COURT: Did the Special Master have to
determine a diagnosis? [THE GOVERNMENT]: No. . . . [PETITIONERS]: [W]e would agree
that . . . petitioner[s] can establish the burden . . . and causation without a diagnosis.”). The
issue of whether the H.H. suffered a vaccine-aggravated injury is properly addressed by Loving
prongs four, five, and six. See W.C. v. Sec’y of Health & Hum. Servs., 704 F.3d 1352, 1357
(Fed. Cir. 2013) (holding Loving to be the “correct framework for evaluating off-table significant
aggravation claims”) (citing Loving ex rel. Loving v. Sec’y of Health & Hum. Servs., 86 Fed. Cl.
135, 144 (2005)). Here, the Special Master did diagnosis, which is permitted under Andreu if the
diagnosis would not arbitrarily change the causation analysis under Loving. Andreu, 569 F.3d at
1381 (“[W]hatever caused [the injury] also led to [petitioner’s] . . . disorder. The pivotal issue,
therefore, is whether the . . . vaccine triggered [the injury].” (internal citation omitted)).
Accordingly, the Court will review to determine if the Special Master’s diagnosis altered
causation prior to a proper causation analysis under Loving. See id.B. Whether H.H.’s Diagnosis Subsumes Causation
An interferonopathy is a genetic autoinflammatory disease. 6 Debora d’Angelo, et al.,
Type I Interferonopathies in Children: An Overview, 9 FRONTIERS IN PEDIATRICS 1, 1 (March 31,
2021). Type I interferonopathy is a subset of interferonopathy diseases. 7 Id. at 2. As of 2017, 13
different type I interferonopathies have been identified. Id. at 6. AGS, one of the first type I
interferonopathies identified, is linked with several genetic mutations and presents in a spectrum
of phenotypes and severity. Id. A person can have a type I interferonopathy that is not AGS or
AGS-like or have a type I interferonopathy with AGS-like symptoms varying in severity. Id.;
see also SM Dec. at 56 (“[A]lthough the AGS diagnostic label still has a useful clinical purpose,
there are many patients who do not fit this paradigm as initially delineated. Hence, we are now
tending towards the use of the generic term ‘type I interferonopathy’” (quoting Crow & Manel at
429)).
Petitioners argue describing the injury as AGS or AGS-like is erroneous because it goes
“against the great weight of evidence presented[.]” Mot. for Review Mem. at 15. While the
Special Master explored nine factors to diagnosis H.H. with AGS or AGS-like interferonopathy,
petitioners maintain there “were more signs or significant characteristics that were not seen in
H.H.” that contradict a finding of AGS. See SM Dec. at 50–60 (discussing nine factors: (1)
clinical presentation; (2) elevated liver enzymes; (3) elevated interferon alpha/neopterin levels;
(4) genetic mutation; (5) calcifications; (6) basal ganglia damage; (7) normalization of neopterin
levels; (8) onset of AGS after 12 months of age; and (9) neurological stabilization and
improvement); Tr. at 20:22–21:1. Specifically, petitioners indicate the lack of a mutation in
H.H., the lack of genes in H.H.’s parents, two healthy siblings, no skin lesions, no calcifications,
no basal ganglia damage, no swallowing issues, no microcephaly, healthy organs, no pleocytosis,
no further regression, perfect skin, and a normal life expectancy all rebut an AGS or AGS-like
6
Interferonopathies are a “group of inherited [(genetic)] autoinflammatory diseases[.]” Debora d’Angelo, et al.,
Type I Interferonopathies in Children: An Overview, 9 FRONTIERS IN PEDIATRICS 1, 1 (March 31, 2021).
7
Type I interferonopathies relate to an overproduction or underproduction of type I interferons who “primarily
participate[] in the innate immune system response to viral antigens[.]” d’Angelo, et al., supra note 10, at 2.
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diagnosis. Tr. at 20:16–22:1. Petitioners assert the Special Master diagnosed H.H. with AGS
when an AGS diagnosis “really seems like well beyond one in a million” and “despite no
medical providers who treated H.H. diagnosing him with AGS.” Mot. for Review Mem. at 15
(citing Entitlement Hr’g Tr. at 290:9–291:15) (emphasis removed); Tr. at 30:1–6
(“[PETITIONERS]: AGS is a diagnosis, is a rare genetic disorder, and that is what the Special
Master . . . diagnosed him with . . . despite no medical providers who . . . treated H.H.
diagnosing him with AGS.”).
In this case, the Special Master determined after assessing nine factors H.H. had a
“genetic type I interferonopathy that is either AGS or is AGS-like.” SM Dec. at 51–60, 63. The
Special Master noted “[m]utations in . . . [seven] genes account for around 95% of patients with
classical AGS . . . mean[ing] . . . five percent of AGS cases are associated with an unidentified
genetic mutation.” Id. at 55 (internal citations omitted). Despite H.H. not having “a gene
currently identified with AGS,” the Special Master still determined H.H. has “AGS or a similar
genetic disorder.” Id. at 55, 51. As the Special Master noted, “[s]everal of H.H.’s treating
physicians . . . agreed that H.H.’s clinical presentation was suggestive of or consistent with
AGS[,]” but no treating physician or AGS expert has been able to definitively diagnosis H.H.
with AGS. Id. at 52. The Special Master, however, did diagnose H.H. with an AGS disorder
despite no treating physician, AGS expert, or medical expert being able to. Id. at 52, 60 (“Dr.
[V]anderver, one of the nations’ leading authorities on AGS, . . . noted that H.H. had a
‘suspected heritable interferonopathy.’”); see also Entitlement Hr’g Tr. at 296:1–4 (“[DR.
BARAÑANO]: I’m not here to say . . . he definitely has AGS. He has something like AGS that
in my experience we will eventually find the genetic underpinnings of his disorder.”).
Whether the diagnosis is correct or not does not change the preliminary issue—whether
the vaccine significantly aggravated H.H.’s injury. As established in Andreu, a determination of
a diagnosis is not required when it does not change the underlying causation dispute; because a
diagnosis may not change the outcome, however, it could be harmless. See supra Section VI.A;
Andreu, 569 F.3d 1367. Therefore, the focus of the Court’s inquiry is if the Special Master
foreclosed a finding of significant aggravation by diagnosing H.H. Andreu, 569 F.3d 1367.
Petitioner argued the diagnosis excludes a fair significant aggravation analysis because
the mischaracterized diagnosis permeates throughout all prongs of the Loving analysis. Mot. for
Review Mem. at 14 (“The [d]ecision denying entitlement in this case rests largely with the
Special Master diagnosing . . . H.H. with AGS or some other unknown genetic [t]ype I
[i]nterferonopathy.”). Petitioners object to the Special Master diagnosing H.H. with an AGS or
AGS-like disorder because it “improperly mischaracterized the meaning of ‘AGS-like’ to
suggest . . . H.H. had a genetic [t]ype I [i]nterferonopathy as opposed to the October 2013
vaccinations causing the [t]ype I [i]nterferonopathy.” Id. The mischaracterization assumed the
genetic mutation solely caused the injury when petitioners argued the injury could be genetic
with a vaccine-aggravated injury in addition to the genetic injury. Id. “[T]he Special Master’s
methodology when analyzing Loving Prongs 4–6” was erroneous because of that assumption. Id.
at 1. In oral argument, petitioners explained “‘AGS-like’ is describing the injury” with
symptoms, but “not all interferonopathies have [AGS symptoms] or have a diagnosis of AGS.”
Tr. at 11:21–25. Petitioners’ theory is H.H. has “an unknown genetic type I interferonopathy.”
Tr. at 8:19–20, 10:17–19, 12:10–14 (“THE COURT: [I]f there was a genetic component,
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petitioners’ argument is it was not AGS? [PETITIONERS]: Correct.”). The Special Master,
according to petitioners, regarded the injury as a normal course of AGS merely because the
symptoms were AGS-like. Mot. for Review Mem. at 14. Petitioners assert this characterization
disregards the possibility of a vaccine-aggravated injury compounding a pre-existing type I
interferonopathy. Tr. at 31:1–5 (“THE COURT: [I]s it that the error was associated with
conflating [injury and diagnosis]? That here . . . the injury as a diagnosis got merged together,
and then the cause became purely genetic? [PETITIONERS]: Yes, Your Honor.”).
The government argues the diagnosis from the Special Master was not incorrect, and
H.H.’s injury is 100 percent caused by H.H.’s unidentified genetic mutation. Tr. at 17:1–20
(“[THE GOVERNMENT]: Special Master Oler went through, very detailed, replying on the
expert reports, relying on the medical record, and the nine factors she provided was how she was
able to come to this conclusion of AGS or AGS-like disease.”), 11:8-11 (“THE COURT: [T]he
government’s position is 100 percent genetic-caused injury? [THE GOVERNMENT]: That is
correct, Your Honor.”). The government asserts H.H.’s injury is consistent with the “normal
course of AGS” and “all because of the genetics.” Tr. at 15:10–21.
The Vaccine Act focuses on tracing causation to the vaccine. The Federal Circuit has
instructed “special masters are not ‘diagnosing’ vaccine-related injuries[,]” but rather “[t]he sole
issues for the special master are, based on the record evidence as a whole and the totality of the
case, whether it has been shown by a preponderance of the evidence that a vaccine caused the
child’s injury[.]” Knudsen ex rel. Knudsen v. Sec’y of Health & Hum. Servs., 35 F.3d 543, 549
(Fed. Cir. 1994) (citing 42 U.S.C. § 300aa-13(a)(1), (b)(1)). A petitioner can allege the vaccine
caused a new injury or the vaccine significantly aggravated an existing injury. Sharpe v. Sec’y of
Health & Hum. Servs., 964 F.3d 1072, 1078 (Fed. Cir. 2020). “[U]ntil science provides us with
better answers, it is not the place of a court to assume that a child with a genetic mutation is
destined to have a severe outcome.” Id. at 1084 n.4. Additionally, the Federal Circuit has
warned against attributing all symptoms or injuries to a single cause. Knudsen, 35 F.3d at 550.
In Knudsen, the Federal Circuit stated,
[p]etitioners need not explain all other symptoms or injuries by reference to
the . . . vaccination, and the issue in vaccine cases is not to diagnose all the injuries
and symptoms of the child in order to ascertain whether the diagnosis is . . . vaccine
or something else. It is entirely plausible, and contemplated by the statute, that [the
vaccine] may cause an [injury] at the same time that . . . something else causes
[other] symptoms or injuries.
Id. In other words, case law allows for recovery of vaccine-caused injuries, whether new or the
result of exacerbating a pre-existing condition. Id.By mischaracterizing H.H.’s injury as a rare AGS or AGS-like interferonopathy, the
Special Master attributed all of H.H.’s injury symptoms to a genetic disease when H.H.’s
existing genetic injury could have been aggravated by the vaccine. The Special Master noted
“additional research has led those who study [AGS] to recognize that ‘the range of phenotypes
associated with mutations’ of AGS genes ‘is much broader than previously realized[,]’ . . . [and
i]t is important to consider this expanded understanding of the AGS phenotype in analyzing
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H.H.’s presentation.” SM Dec. at 55–56. In other words, the Special Master recognized a
scientific understanding of AGS and AGS-like mutations was ongoing, and the presentation of
AGS was broadening to include a spectrum of symptoms (or lack of symptoms) and severities.
Id. Consequently, an AGS or AGS-like diagnosis “assume[s] that a child with a genetic
mutation is destined to have a severe outcome” even if a portion of the severity or symptoms
could be attributed to vaccine aggravation. See Sharpe, 964 F.3d at 1084 n.4. The broad
characterization of symptoms as an AGS or AGS-like diagnosis effectively eliminated the
possibility of “the October 2013 vaccinations [significantly aggravating] the [t]ype I
[i]nterferonopathy” even though Pentacel may have caused H.H.’s injury at the same time H.H.’s
genetic mutation caused similar symptoms or injuries because the decision does not account for
H.H.’s baseline if he only had an AGS or AGS-like disorder. Mot. for Review Mem. at 14; see
Knudsen, 35 F.3d at 550 (“[T]he issue in vaccine cases is not to diagnose all the injuries and
symptoms of the child in order to ascertain whether that diagnosis is . . . vaccine or something
else.”); see also Sharpe, 964 F.3d at 1087 (“Congress envisioned that children with pre-existing
conditions, such as gene mutations, could potentially recover.”). Accordingly, the Court will
assess Loving prongs four, five, and six to determine if the diagnosis led to an arbitrary and
capricious finding on vaccine aggravation. See Knudsen, 35 F.3d at 550.
VII. The Special Master’s Analysis for Significant Aggravation under Loving
To establish causation, a petitioner can “allege that the vaccine caused the onset of [the]
injuries (an onset claim) or that the vaccine significantly aggravated [a] pre-existing condition (a
significant aggravation claim).” Sharpe v. Sec’y of Health & Hum. Servs., 964 F.3d 1072, 1078
(Fed. Cir. 2020). For an onset claim, a petitioner must satisfy by preponderant evidence the
three-prong Althen analysis. Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274, 1278 (Fed.
Cir. 2005). For a significant aggravation claim, a petitioner must satisfy by preponderant
evidence the Loving six-part test. Loving ex rel. Loving v. Sec’y of Health & Hum. Servs., 86
Fed. Cl. 135, 144 (2009). The last three prongs of Loving are derived from Althen and make up
the “causation in fact” analysis. W.C. v. Sec’y of Health & Hum. Servs., 704 F.3d 1352, 1357
(Fed. Cir. 2013) (“The Loving test combines the first three Whitecotton factors, which establish
significant aggravation, with the Althen factors, which establish causation.”). The Althen/Loving
frameworks are the established vehicles in which to analyze causation in fact. See id. (holding
Loving provides the correct framework for analyzing off-table significant aggravation claims);
see also Althen, 418 F.3d at 1278. In this case, the Special Master found a “physical sign
of . . . type I interferonopathy” prior to H.H.’s Pentacel vaccination. SM Dec. at 72; see supra
Section V.B. Under Locane, the Special Master’s finding eliminated an onset claim and left only
a significant aggravation claim. Locane v. Sec’y of Health & Hum. Servs., 685 F.3d 1375, 1381
(Fed. Cir. 2012) (If “the illness was present before the vaccine was administered, logically, the
vaccine could not have caused the illness.”); see supra Section V.B.
The Special Master analyzed the first three prongs of Loving and found “H.H.’s
deterioration is consistent with the Vaccine Act’s definition of significant aggravation[.]” SM
Dec. at 63. Petitioners objected only to the last three prongs of the Special Master’s Loving
analysis—the three prongs of Althen. Mot. for Review Mem. at 11 (“The [d]ecision . . .
improperly concluded the [p]etitioners did not meet the burden of proof to establish Loving
[p]rongs 4, 5, & 6 . . . .”).
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When the Special Master’s diagnosis inadvertently foreclosed a significant aggravation
claim, the causation analysis may have become arbitrary. See supra Section VI.B. The
government asserts if the diagnosis was incorrect, it was harmless error because “the [S]pecial
[M]aster found that petitioners failed to meet their burden under any of the three Althen prongs,
and a failure to meet their burden under even one is dispositive and fatal to their case.” Resp’t’s
Resp. at 14. If the diagnosis subsumes causation, the Special Master may not have performed a
proper causation analysis under Loving. See Knudsen ex rel. Knudsen v. Sec’y of Health & Hum.
Servs., 35 F.3d 543, 550 (Fed. Cir. 1994) (“[T]he issue in vaccine cases is not to diagnose all the
injuries and symptoms of the child in order to ascertain whether that diagnosis is . . . vaccine or
something else.”); see also supra Section VI.B. Accordingly, the Court must determine whether
the diagnosis caused the Special Master’s analysis of Loving prongs four, five, and six to be
arbitrary and capricious.
A. Petitioners’ Medical Theory Under Loving Prong Four
“Under Loving prong [four], a petitioner need only provide ‘a medical theory causally
connecting [petitioner’s] significantly worsened condition to the vaccination.’” Sharpe, 964 F.3d
at 1083 (quoting Loving, 86 Fed. Cl. at 144). “While it does not require medical or scientific
certainty, [the explanation] must still be ‘sound and reliable.’” Boatmon v. Sec’y of Health &
Hum. Servs., 941 F.3d 1351, 1359 (Fed. Cir. 2019) (quoting Knudsen, 35 F.3d at 548–49).
Where medical literature or epidemiological evidence is introduced, it must not be viewed
“through the lens of the laboratorian, but instead from the vantage point of the Vaccine Act’s
preponderant evidence standard[.]” Andreu ex rel. Andreu v. Sec’y of Health & Hum. Servs., 569
F.3d 1367, 1380 (Fed. Cir. 2009).
The Special Master found “[p]etitioners have not presented . . . a reputable explanation in
this case; as such, they have failed to present preponderant evidence in support of Loving prong
four . . . ” SM Dec. at 68. Petitioners’ second objection alleges the Special Master “fail[ed] to
recognize [p]etitioners’ experts’ medically sound theory of causation of injury[.]” Mot. for
Review Mem. at 1. Petitioners assert Dr. Steinman “produced med[ical] literature that supports
his theory that [vaccinations] can cause the production of interferon,” and “experts agree that
overproduction or an excessive amount of interferons can cause the type of injury seen in
[H.H.].” Id. at 16. The government asserts petitioners “provided a wholly speculative theory
that was not supported by the scientific literature[,]” and even if petitioners “had provided
sufficient evidence to establish that Dr. Steinman’s theory was possible, that would not have
been sufficient to meet their burden.” Resp’t’s Resp. at 10.
A special master’s decision is often “based on the credibility of the experts and the
relative persuasiveness of their competing theories.” Broekelschen v. Sec’y of Health & Hum.
Servs., 618 F.3d 1339, 1347 (Fed. Cir. 2010). “[I]t is not . . . the role of this court to reweigh the
factual evidence, or to assess whether the special master correctly evaluated the evidence.”
Munn v. Sec’y of Health & Hum. Servs., 970 F.2d 863, 871 (Fed. Cir. 1992). “If the special
master has considered the relevant evidence of record, drawn plausible inferences and articulated
a rational basis for the decision, reversible error will be extremely difficult to demonstrate.”
Hines ex rel. Sevier v. Sec’y of Health & Hum. Servs., 940 F.2d 1518, 1528 (Fed. Cir. 1991). A
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special master, however, cannot “cloak the application of an erroneous legal standard in the guise
of a credibility determination, and thereby shield it from appellate review.” Andreu, 569 F.3d at
1379.
Petitioners here had two occasions to provide a reputable medical theory. See SM Dec. at
71 n.28. First, petitioners postulated a now abandoned molecular mimicry theory. 8 Id. After the
hearing, and at the suggestion of the Special Master, petitioners retained Dr. Lawrence Steinman,
an expert neurologist. Pet’rs’ Status Rep. of 14 April 2020 at 1. Dr. Steinman submitted an 18-
page report and 4-page reply report “focuse[d] on ‘how the components of the [Pentacel] vaccine
can drive an interferon response.’” SM Dec. at 39 (quoting Steinman Rep. at 9). Dr. Steinman
posited the pertussis toxin and alum found within Pentacel can cause an increase of interferons
directly or through the activation of inflammasomes. Steinman Rep. at 12–13. Where a patient
has a resistance to type I interferons, the activation of inflammasomes causes overproduction of
type I interferons and worsens neuroinflammation. Id. at 14. Additionally, any imbalance of
type I and type II interferons can exacerbate a type I interferonopathy. Id. Dr. McGeady, the
government’s expert who previously submitted a report and testified at the entitlement hearing,
submitted a 3-page rebuttal report. Second McGeady Rep.
The first study petitioners’ expert Dr. Steinman referenced is a 2014 paper about immune
responses to pertussis antigens in infants and toddlers after DTaP vaccination, first authored by
lead researcher Fadugba. Steinman Rep. at 12 (citing Olajumoke Fadugba et al., Immune
Responses to Pertussis Antigens in Infants and Toddlers after Immunization with
Multicomponent Acellular Pertussis Vaccine, 21 CLINICAL AND VACCINE IMMUNOLOGY 12, 1613
(2014), ECF No. 101-12 [hereinafter Fadugba]). Fadugba is not a study of AGS or a study
where the subjects have a pre-existing interferonopathy. Fadugba at 1613–16. Dr. Steinman
reviewed this research to conclude “[p]ertussis toxin induces immune responses to both
gamma-interferon and to type I interferon.” Steinman Rep. at 12. The government’s expert, Dr.
McGeady, did not address the Fabugba research directly in his rebuttal report, and the
government agreed at oral argument Dr. McGeady did not reference it at all. Second McGeady
Rep.; Tr. at 40:3–8. Dr. McGeady, however, “do[es] not question the assertion that component
of Pentacel (and of all vaccines) activate the innate immune system . . . [and the] sequence would
be expected to generate a physiologic amount of type I interferon[s.]” Second McGeady Rep. at
2–3. The Special Master’s decision did not dispute the Fadugba conclusions, agreed with the
study generally, and noted it “stand[s] for the proposition that DTaP vaccination results in an
increase in gamma interferon[.]” SM Dec. at 65. As the study’s results relate to H.H., the
Special Master attempted to distinguish the Fadugba study based on the timing of study
measurements and noted “these [study] levels were not measured until one month after the
booster vaccination.” Id. The Special Master did not explain how the timing of the study was
consequential, and exactitude in study-to-petitioner injury timing is not part of the medical
theory requirement under Loving prong four. See Sharpe, 964 F.3d at 1083 (“Under Loving
prong [four], a petitioner need only provide a medical theory causally connecting [petitioner’s]
significantly worsened condition to the vaccination.” (internal quotations omitted)); SM Dec. at
65. At oral argument, when pressed on the importance of the Fadugba research as it relates to
8
At the conclusion of the entitlement hearing, the Special Master “informed [p]etitioners’ counsel that the record, as
it currently stood, did not enable [p]etitioners to meet their burden” and “suggested . . . retaining an additional expert
neurologist[.]” SM Dec. at 4 n.7.
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Loving prong four, the government also agreed Fadugba “show[s] there is an increase” as Dr.
Steinman concludes. Tr. at 39:10–23 (“THE COURT: Does the government agree with the
Special Master’s finding that Fadugba supports Dr. Steinman’s theory? [THE
GOVERNMENT]: . . . [Y]es, it does show that there is an increase[.]”). Petitioners must prove
their medical theory “by a preponderance of the evidence[,]” and petitioners offered Fadugba to
support their medical theory. Loving, 86 Fed. Cl. at 143–44. While not conclusive by itself, the
Special Master’s—and the government’s—agreement Fadugba supports the “proposition that
DTaP vaccination results in an increase of gamma interferon” carries significant weight in favor
of petitioners satisfying their burden to prove “a medical theory causally connecting the
vaccination and the [significant aggravation]” is “more probable than not.” SM Dec. at 65;
Loving, 86 Fed. Cl. at 144 (quoting Althen, 418 F.3d at 1278).
The second study referenced by Dr. Steinman in support of his medical theory is a 2018
study summarizing research about the modulating effect of vaccine antigens on the body’s innate
immune response conducted by lead researcher and author Kooijman. Steinman Rep. at 12
(citing Sietske Koojiman et al., Vaccine antigens modulate the innate response of monocytes to
Al(OH)3, PLOS ONE 13:e0197885 (2018), ECF No. 101-13 [hereinafter Kooijman]). The
research was performed with human blood samples whose donors did not have AGS or an
interferonopathy. Kooijman at 2–3. Dr. Steinman utilizes Kooijman to show “DTaP induces
type I interferons” and stimulates an “increased gene expression of [a] type I interferon[.]”
Steinman Rep. at 12 (internal quotations omitted). Dr. McGeady did not directly address
Kooijman or its proposition but indicated he agreed Pentacel “activate[s] the innate immune
system” which in turn “generate[s] a physiologic amount of type I interferon[.]” Second
McGeady Rep. at 2–3; Tr. at 43:2–5 (“THE COURT: You agree Dr. McGeady does not put
forth any rebuttal evidence? [THE GOVERNMENT]: Specifically towards [Kooijman], not in
his supplemental expert report.”). The government agreed at oral argument the article supports
an increase of interferons caused by vaccinations, but the government argued the article has not
“shown that it is a plausible theory” because “it’s incomplete.” Tr. at 43:10–15. Under Loving
prong four, not only is medical literature not required to prove a medical theory, but also a single
piece of medical literature, like Koojiman, is not required to “identif[y] and [prove] specific
biological mechanisms[.]” Knudsen, 35 F.3d at 549 (“[C]ausation can be found in vaccine cases
. . . without detailed medical and scientific exposition on the biological mechanisms. . . . [T]o
require identification and proof of specific biological mechanisms would be inconsistent with the
purpose and nature of the vaccine compensation program.”). The Special Master did not dispute
the findings in Kooijman but quoted Kooijman, stating, “[a]fter 24 hours of stimulation, both
Al(OH)3 and DTaP-stimulated monocytes showed a trend towards increased gene expression of
[a] type I interferon[.]” SM Dec. at 65. Under Loving, petitioner must show a “medical theory
causally connecting the vaccination and the [significant aggravation]” is “more probable than
not.” Loving, 86 Fed. Cl. at 144 (quoting Althen, 418 F.3d at 1278). The Special Master’s
agreement with Kooijman’s proposition DTaP induces type I interferons adds further support,
along with Fadugba, in favor of petitioners satisfying their burden to prove a “medical theory
causally connecting the vaccination and the [significant aggravation]” is “more probable than
not.” See SM Dec. at 65 (citing Kooijman); Loving, 86 Fed. Cl. at 144 (quoting Althen, 418 F.3d
at 1278).
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A 2008 study summarizing the research regarding inflammasome activation by alum
conducted by lead researcher and author Li is the third piece of medical literature explained and
applied by Dr. Steinman. Steinman Rep. at 12 (citing Hanfen Li et al., Cutting Edge:
Inflammasome Activation by Alum and Alum’s Adjuvant Effect Are Mediated by NLRP3, 181 J.
IMMUNOLOGY 17, 18 (2008), ECF No. 101-14 [hereinafter Li]). Li discusses a study done with
mice and human macrophage cell lines without AGS or an interferonopathy given a tetanus
toxoid and diphtheria toxoid vaccine comprising alum. Li at 18. Dr. Steinman discussed Li to
conclude “alum in Pentacel . . . activat[es] the[] NALRP3 inflammasome, which plays a key role
in inducing interferonopathies[.]” Steinman Rep. at 12. Specifically, Dr. Steinman used Li to
show “[i]nflammation induced by innate immunity influences the development of T
cell-mediated autoimmunity” which in turn creates an increase of interferons. Id. (internal
quotations omitted). Dr. McGeady did not directly address whether the “alum in Pentacel . . .
plays a key role in inducing interferonopathies,” and at oral argument, the government was
unable to answer whether Dr. McGeady specifically rebutted the Li study. See Steinman Rep. at
12; Tr. at 45:1–6. The government at oral argument agreed Li supports the notion “vaccines may
activate . . . the inflammasome[.]” Tr. at 45:1–6. The Special Master quoted Li for the
proposition “inflammasome activation by alum and alum’s adjuvanticity are mediated by NLRP3
and ASC.” SM Dec. at 65 (citing Li). The Special Master continued, “[i]n conclu[sion], [Li]
noted that . . . NLRP3 [is] an important player in alum’s adjuvant effect and [Li’s results]
indicate an important role for the inflammasome in the development of adaptive immunity.” Id.at 65–66 (internal quotations omitted). The Special Master’s decision did not dispute Li’s
conclusions. Id. at 65. A petitioner must prove a “medical theory causally connecting the
vaccination and the [significant aggravation]” by preponderant evidence. Loving, 86 Fed. Cl. at
144 (quoting Althen, 418 F.3d at 1278). Li and the Special Master’s adoption of Li’s conclusion
identifying “NLRP3 as an important player in alum’s adjuvant effect . . . and [the] role for the
inflammasome in the development of adaptive immunity [(the body’s immune response)]” weigh
in favor of petitioners satisfying their requirement to prove by preponderant evidence “a medical
theory causally connecting the vaccination and the [significant aggravation.]” SM Dec. at 65
(citing Li); Loving, 86 Fed. Cl. at 144 (quoting Althen, 418 F.3d at 1278).
The fourth and fifth papers, both co-authored and referenced by Dr. Steinman, are the
2016 Inoue paper, summarizing studies researching the molecular and cellular mechanisms of
the NLRP3 inflammasome pathway performed by lead researcher and primary author Inoue, and
the 2013 Axtell paper, a review article summarizing various research studies regarding type I
interferons in autoimmune diseases with primary author Axtell. Steinman Rep. at 12 (citing
Makato Inoue et al., Mechanisms to develop inflammasome-independent and
interferon-β-resistant EAE with neuronal damages, 19 NAT. NEUROSCI. 12, 1599–1609 (2016),
ECF No. 101-15 [hereinafter Inoue]; Robert Axtell et al., Type I Interferons: Beneficial in Th1
and Detrimental in Th17 Autoimmunity, 44 CLINICAL REV. ALLERGY IMMUNOLOGY 2, 114–20
(2013), ECF No. 101-16 [hereinafter Axtell]). The Inoue research was done is in the context of
experimental autoimmune encephalitis (“EAE”) in mice and multiple sclerosis (“MS”) in human
blood cells. Inoue at 2, 7. Axtell reviewed interferon type I activity in a variety of autoimmune
diseases including MS. Axtell at 1. Dr. Steinman reviewed Inoue to show “there are interferon
responsive neuroinflammatory conditions[.]” Steinman Rep. at 12. Dr. Steinman discussed
Axtell to demonstrate “there [is a] resistance to the therapeutic effect of type I interferon in
neuroinflammation, [and] in some conditions interferon can worsen the neuroinflammation[.]”
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Id. In the case of H.H., whom the Special Master diagnosed with an AGS or AGS-like
neuroinflammatory disorder, the immunization would have “worsened neuroinflammation in
H[.]H.” Steinman Reply at 3. The government was unable to “point the Court to . . . specific
references” to either article in Dr. McGeady’s rebuttal or evidence that Dr. McGeady addressed
the studies directly at all. Tr. at 54:19–55:21 (“THE COURT: [I]s that even possible to
distinguish, him addressing [Inoue or Axtell]? [THE GOVERNMENT]: I could not point the
Court to . . . specific references. I would say he just addresses their overall point.”). The Special
Master recognized Dr. Steinman used Inoue and Axtell for the “proposition that inflammasome
activation can worsen neuroinflammation” but attempted to distinguish Inoue and Axtell
because they “discuss[] [EAE] and [MS.]” SM Dec. at 66. Dr. McGeady, however, does not
discount the study based on the EAE or MS distinction. Tr. 49:8–16 (the government stating Dr.
McGeady had “no specific mention” of Inoue). Petitioners are merely required to “provide a
medical theory causally connecting [petitioner’s] significantly worsened condition to the
vaccination.” Sharpe, 964 F.3d at 1083 (internal quotations omitted). Petitioners provided Inoue
and Axell in support of their medical theory, and the Special Master agreed Inoue and Axtell
show “inflammasome activation can worsen neuroinflammation[,]” albeit in EAE and MS,
which adds additional support to petitioners’ requirement to show “a medical theory causally
connecting [H.H.’s] significantly worsened condition to the vaccination” through preponderant
evidence. See id.; SM Dec. at 66.
The sixth piece of medical literature co-authored and utilized by Dr. Steinman was the
2013 Naves study summarizing research on the roles of type I and type II interferons in
modulating autoimmune neuroinflammation. Steinman Rep. at 14 (citing Rodrigo Naves et al.,
The Interdependent, Overlapping, and Differential Roles of Type I and II IFNs in the
Pathogenesis of Experimental Autoimmune Encephalomyelitis, 191 J IMMUNOL., 2967–77
(2013), ECF No. 101-17 [hereinafter Naves]). Dr. Steinman reviewed Naves to “emphasize[] the
intricate interplay of type [I] and type [II] interferons on neuroinflammation[.]” Id. In H.H.’s
case, he “has a continued propensity to overproduce type [I] interferon[s],” so additional
imbalance of interferons can exacerbate or lead to enhanced severity. Id. Dr. McGeady does not
address Naves directly. See Second McGeady Rep. The Special Master stated Naves
“support[s] the principle that imbalance in interferon signaling aggravates disease in EAE” but
found because EAE is the animal model for MS and not interferonopathy, “[i]t is difficult to see
how this point is persuasive[.]” SM Dec. at 67. Under Loving, petitioners were required to
present evidence of a “medical theory causally connecting the vaccination and the [significant
aggravation.]” Loving, 86 Fed. Cl. at 144 (quoting Althen, 418 F.3d at 1278). Petitioners
provided Naves to support a “medical theory causally connecting the vaccination and the
[significant aggravation]” and the Special Master agreed Naves “support[s] the principle that
imbalance in interferon signaling aggravates disease in EAE[,]” another type of
neuroinflammatory disease like H.H.’s neuroinflammatory interferonopathy. See Loving, 86
Fed. Cl. at 144 (quoting Althen, 418 F.3d at 1278); SM Dec. at 67. While the Special Master
found the study did not apply, petitioners’ use of Naves in combination with other medical
literature further supports a reliable medical theory and petitioners satisfying their “more
probable than not” burden. See Loving, 86 Fed. Cl. at 144.
The seventh piece of medical literature referenced by Dr. Steinman was the 2016 Rodero
& Crow review article surveying previously published research on type I interferonopathies.
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Steinman Rep. at 14 (citing Mathieu Rodero & Yanick Crow, Type I interferon-mediated
monogenic autoinflammation: The type I interferonopathies, a conceptual overview, 213 J.
EXPERIMENTAL MED. 12, 2527–38 (2016), ECF No. 101-18 [hereinafter Rodero & Crow]). Dr.
Steinman reviewed Rodero & Crow for the “general principle that an antecedent infection or
even a vaccination could be the ‘stressor’ that triggered the interferonopathy[.]” Id. In his expert
reply, Dr. Steinman acknowledged “H.H. does not have an ADAR-1 mutation, but the general
principle [of the study] . . . provides a foundation for impugning the immunizations in October
2013.” Steinman Reply at 2. At oral argument, the government asserted Rodero & Crow was
not persuasive because it related to the ADAR subset of AGS. Tr. at 64:11–22 (the government
stating Rodero & Crow was not persuasive “[b]ecause H.H. doesn’t have . . . ADAR, so it
wouldn’t be applicable.”). Dr. McGeady, however, does not make this point in his rebuttal. See
Second McGeady Rep. In fact, Dr. McGeady does not reference the Rodero & Crow article at
all. 9 Id. The Special Master concluded Rodero & Crow “suggests that vaccination as a potential
trigger for a type I interferonopathy involving an ADAR-1 mutation could be an area of study at
some point in the future” but “does not provide persuasive evidence . . . in this case.” SM Dec.
at 67.
The Special Master discredited Naves, Inoue, Axtell, and Rodero & Crow because the
research did not directly study interferonopathies or AGS. Id. at 67–68 (finding Naves, Inoue,
Axtell, and Rodero & Crow unpersuasive because the studies were not directly analogous). The
Federal Circuit has held “‘[i]n a field bereft of complete and direct proof of how vaccine affect
the human body,’ a paucity of medical literature supporting a particular theory of causation
cannot serve as a bar to recovery.” Andreu, 569 F.3d at 1379 (citing Daubert v. Merrell Dow
Pharms., Inc., 509 U.S. 579, 593 (1993) (“[I]n some instances well-grounded but innovative
theories will not have been published . . . . Some propositions, moreover, are too particular, too
new, or of too limited interest to be published.”)). Medical literature is not required to prove a
“medical theory causally connecting the vaccination and the [significant aggravation,]” so “to
require identification and [to prove a] specific biological mechanism[] would be inconsistent
with the purpose and nature of the vaccine compensation program.” Loving, 86 Fed. Cl. at 144(quoting Althen, 418 F.3d at 1278); Knudsen, 35 F.3d at 549. The Special Master acknowledged
“there appears to be no published medical literature (to include case reports) indicating the flu,
pneumonia, or Pentacel vaccines can cause or exacerbate a type I interferonopathy.” SM Dec. at
67. “Dr. McGeady testified that there is also no literature suggesting the live viruses associated
with these vaccines could cause one of these conditions.” Id. (internal citation omitted).
Additionally, during oral argument, the parties were not aware of any other vaccine cases with a
Pentacel or pertussis injury with similar symptoms. Tr. at 62:20–25 (“THE COURT: Are you
aware of any other vaccine cases with a Pentacel or pertussis injury with similar symptoms?
[PETITIONERS]: No, Your Honor. . . . [THE GOVERNMENT]: I am not.”). The Court
makes no finding on the assessment of the medical studies, and given the rare nature of AGS and
H.H.’s condition, the Court notes research on the effect of vaccines on interferonopathies or
AGS may be non-existent, and therefore analogous research may be properly persuasive in this
9
At oral argument, the government asserted Dr. McGeady referenced the Rodero & Crow article on page two of his
expert report. Tr. at 69:8–9. The “Crow” references, however, refer to two other articles authored by Crow
published in 2015 and 2018. See Crow & Manel at 429; Yanick Crow et al., A Brief Historical Perspective on the
Pathological Consequences of Excessive Type 1 Interferon Exposure In vivo, 38 J. CLIN. IMMUNOL. 694 (2018),
ECF No. 71-8.
- 30 -
case. See Andreu, 569 F.3d at 1379 (“[I]n a field bereft of complete and direct proof of how
vaccine affect the human body, a paucity of medical literature supporting a particular theory of
causation cannot serve as a bar to recovery.” (quoting Althen, 418 F.3d at 1280) (internal
quotations omitted)). The Court leaves the question to the Special Master on remand. See id.;
Knudsen, 35 F.3d at 551 (remanding for the Special Master to reassess evidence).
After reviewing Dr. Steinman’s theory, the Special Master credited Dr. McGeady and
found petitioners did not meet their burden of proof. SM Dec. at 66–68. Dr. McGeady in his
rebuttal report, however, did not directly address any of the medical literature put forth by Dr.
Steinman. See Second McGeady Rep. Dr. McGeady—and the Special Master relying on Dr.
McGeady—found Dr. Steinman’s theory unpersuasive for two reasons: (1) “[p]etitioners’ theory
does not explain how vaccination caused H.H.’s innate immune response to be so ‘massively
exaggerated as demonstrated by the elevated levels of interferon alpha in the blood and
cerebrospinal fluid”; and (2) “Dr. Steinman did not explain how H.H.’s interferon alpha levels
remained elevated for years after vaccination.” SM Dec. at 66. The Special Master stated the
literature cited by Dr. Steinman “does not suggest that [the increased interferon levels] are
excessive. . . . Neither [Fadugba nor Kooijman] suggests that interferon production post-DTaP
vaccination is anything resembling H.H.’s interferon alpha levels[.]” Id. Further, the Special
Master found the theory does not explain H.H.’s persistently elevated levels. Id. at 67
(“Petitioners’ theory is equally unpersuasive in preponderantly establishing that vaccination can
cause persistently elevated levels of interferon alpha.”).
The Federal Circuit summarized in Sharpe, a case alleging significant aggravation of
petitioner’s pre-existing encephalopathy, “[p]etitioner [is] required to present a medically
plausible theory demonstrating that a vaccine ‘can’ cause a significant worsening of [the
disorder].” Sharpe, 964 F.3d at 1083. In other words, a petitioner at Loving prong four is not
required to show injury did happen—“did cause” is the subject of prong five—but petitioners
must explain how Pentacel could exacerbate H.H.’s pre-existing AGS or AGS-like disorder,
resulting in greater injury than what H.H.’s baseline was with only AGS. See id.; Loving, 86
Fed. Cl. at 144. The Special Master found “[w]hile vaccines may activate the inflammasome,
Dr. Steinman has not presented a link between such activation and the development of AGS or a
similar type I interferonopathy.” SM Dec. at 66. Petitioners disagreed and pointed specifically
to the Inoue and Axtell studies as support for the link between activation and the development of
AGS. Tr. at 45:23–46:14 (“[PETITIONERS]: The link is that Pentacel can trigger type I and
type II interferon response by triggering the NLRP3 inflammasomes . . . [which] causes an
overproduction of interferon, and that can be explained. . . . [by] a resistance in some forms of
neuroinflammation to the normal beneficial response of interferons. . . . [U]nchecked interferon
production drives neuroinflammation, which then can cause severe central nervous system
damage.”), 46:19–24 (petitioners agreeing Dr. Steinman showed a link between inflammasome
activation and a development of AGS or similar type I interferonopathy). The question here is
not whether there was “activation and . . . development of AGS or a similar type I
interferonopathy” as the Special Master suggested but rather if the Pentacel vaccine could have
caused additional injury on top of H.H.’s pre-existing type I interferonopathy. See Sharpe, 964
F.3d at 1083; SM Dec. at 66. The Special Master also rejects Dr. Steinman’s medical theory
because of what actually happened—persistent, elevated levels—in H.H.’s case; this reasoning
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confuses the prong-four requirement with the prong-five requirement. See Sharpe, 964 F.3d at
1083.
Petitioners’ expert, Dr. Steinman, did provide a theory supported by medical research
explaining the Pentacel vaccine can cause an increase in interferons as a normal innate immune
response and through activation of inflammasomes, which “would be additive to what is
already . . . ongoing in [H.H.].” Steinman Reply at 2. For H.H., “an underlying AGS
condition”—a neuroinflammation disease which by its nature already increases interferon
production—would have worsened with the administration of the vaccination. Id. at 3. Dr.
Steinman utilized Fadugba and Kooijman as support in explaining the pertussis toxin in the
Pentacel vaccine could cause an increase in interferons. Steinman Rep. at 12. The Special
Master attempted to distinguish Fadugba due to the timing of measurements but did not explain
how timing was consequential or why an exactitude in study-to-petitioner injury timing is
required under Loving. See Sharpe, 964 F.3d at 1083 (“Under Loving prong [four], petitioners
need only provide a medical theory causally connecting petitioner’s significantly worsened
condition to the vaccination.” (internal quotations omitted)); SM Dec. at 65. Accordingly, the
Special Master’s finding on timing was arbitrary and capricious and therefore error. Dr.
Steinman reviewed Li to show alum, a component of Pentacel, can trigger a type I or type II
interferon response or increase by triggering the NLRP3 inflammasomes and the activation of
inflammasomes. Steinman Rep. at 12. Dr. Steinman reviewed Inoue and Axtell to show
resistance to type I interferons and inflammasome activation can worsen neuroinflammation, like
an AGS or AGS-like disorder. Id. Dr. Steinman utilized Naves to support the notion any
imbalance of type I and type II interferons can exacerbate a type I interferonopathy, a
pre-existing condition H.H. was purported to have. Id. at 14. Lastly, Dr. Steinman reviewed
Rodero & Crow to support the proposition of a vaccination triggering an interferonopathy. Id.
While one piece of medical literature by itself does not necessarily establish a reliable medical
theory, the principles supported by the research studies discussed by Dr. Steinman—and the
Special Master’s general agreement with the research studies’ propositions—cumulatively carry
significant weight in favor of petitioners satisfying their burden to prove “a medical theory
causally connecting the vaccination and the [significant aggravation]” that is “more probable
than not.” See Sharpe, 964 F.3d at 1083 (“Under Loving prong [four], a petitioner need only
provide a “medical theory causally connecting [petitioner’s] significantly worsened condition to
the vaccination.’” (emphasis added)).
The arbitrary and capricious standard “is a highly deferential standard of review[:] [i]f
the special master has considered the relevant evidence of record, drawn plausible inferences and
articulated a rational basis for the decision, reversible error will be extremely difficult to
demonstrate.” Hines, 940 F.2d at 1528. Here, the Special Master agreed “the literature cited by
Dr. Steinman does demonstrate that vaccination causes the production of some amount of
interferon” yet did not find petitioners met their burden to prove their “medical theory causally
connecting the vaccination and the [significant aggravation]” is “more probable than not.” SM
Dec. at 66, 68; see Sharpe, 964 F.3d at 1083. Dr. Steinman opined “if there was an underlying
AGS condition in play in H[.]H[.], . . . the immunization would have worsened
neuroinflammation in H[.]H.” Steinman Reply at 3. As discussed supra, Dr. Steinman’s
medical theory cited seven related research studies supporting his expert conclusions. Steinman
Rep. at 12–14. While the Special Master concluded petitioners did not prove a medical theory
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for significant aggravation, the analysis did not address H.H.’s pre-existing condition or what
H.H.’s normal AGS baseline would be when the Special Master generally discredited Dr.
Steinman’s theory as not suggesting “anything resembling H.H.’s interferon alpha levels” or the
“persistently elevated levels of interferon alpha”—when some degree of persistent elevated
interferon level is a characteristic of a baseline AGS or AGS-like disorder. SM Dec. at 66–67.
Disregarding H.H.’s pre-existing condition when analyzing whether Pentacel could worsen
H.H.’s condition and discarding Dr. Steinman’s theory positing Pentacel “would have worsened
neuroinflammation” is error. 10 Sharpe, 964 F.3d at 1086 (“A significant aggravation claim, by
definition, requires a petitioner to have a pre-existing injury.” (quoting Loving, 86 Fed. Cl. at
144)), 1080 (“[A] petitioner must establish . . . ‘a medical theory causally connecting such a
significantly worsened condition to the vaccination[.]’”) (quoting Loving, 86 Fed. Cl. at 144));
Steinman Reply at 3 (“[T]he immunization would have worsened neuroinflammation in
H[.]H.”); SM Dec. at 53–55, 57–58, 66–67 (concluding petitioners “failed to present
preponderant evidence in support of Loving prong four” because petitioners could not explain
persistent elevated levels—a symptom present in AGS). This consideration is especially
pronounced because the government agreed their expert Dr. McGeady did not address any of the
research Dr. Steinman’s opinion extensively reviewed supporting his medical theory. Tr. at
40:3–8 (“THE COURT: Did your expert, Dr. McGeady, cite to any medical studies that rebut
Fadugba? [THE GOVERNMENT]: Not for the proposition that there is an increase[.]”), 43:2–5
(“THE COURT: You agree Dr. McGeady does not put forth any rebuttal evidence [to
Kooijman]? [THE GOVERNMENT]: Specifically towards [Kooijman], not in his supplemental
expert report.”), 54:19–55:21 (“THE COURT: [I]s that even possible to distinguish, him
addressing [Inoue or Axtell]? [THE GOVERNMENT]: I could not point the Court to . . .
specific references. I would say he just addresses their overall point.”), 55:18–21 (“[THE
COURT]: Do you agree that Dr. McGeady does not address [Axtell] directly? [THE
GOVERNMENT]: I agree he does not address Axtell directly.”); see Tr. at 45:1–6 (the
government unable to answer where Li is rebutted). The Court finds the Special Master’s
conclusion regarding Loving prong four is accordingly unsupported in discussion with the
medical literature, was not evaluated in light of a significant aggravation claim, and is therefore
arbitrary and capricious. See Saunders v. Sec’y of Health & Hum. Servs., 25 F.3d 1031, 1033
(Fed. Cir. 1994) (“Fact findings are reviewed . . . under the arbitrary and capricious standard;
legal questions under the ‘not in accordance with law’ standard; and discretionary rulings under
the abuse of discretion standard.”); see also Paluck v. Sec’y of Health & Hum. Servs., 786 F.3d
1373, 1380 (Fed. Cir. 2015) (“Where, as here, a special master . . . makes factual inferences
wholly unsupported by the record, the Court of Federal Claims is not only authorized, but
10
The Special Master’s decision either does not contemplate H.H.’s pre-existing condition and already elevated
interferons or attributes the full severity of his injury to an unidentified genetic mutation, foreclosing a significant
aggravation claim. SM Dec. at 55 (“[T]here was no explanation for H.H.’s elevated neopterin and interferon alpha
levels other than AGS.”), 56 (adopting an “expanded understanding of the AGS phenotype” to include all of H.H.’s
current symptoms as part of his AGS or AGS-like disorder), 58 (crediting the opinions of Drs. McGeady and
Barañano stating there is “variability in AGS presentation” and “normal development before the onset of symptoms
in AGS . . . should not be considered as a finding implicating the vaccines”), 60 (attributing “H.H.’s rapid and
relentless decline” to the start of the disease process rather than a potential vaccine aggravation), 66 (discrediting Dr.
Steinman’s theory because it did explain excessive interferon levels, a symptom characteristic of AGS, when H.H.’s
interferon alpha levels were “the highest neopterin levels [one provider had] ever seen”), 67 (discrediting Dr.
Steinman’s theory because it did not address “persistently elevated levels[,]” a symptom characteristic of AGS and a
component of H.H.’s condition).
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obliged, to set aside the [S]pecial [M]aster’s findings of fact and conclusions of law.”). The
Court leaves the ultimate conclusion to the Special Master on remand regarding whether H.H.’s
pre-existing condition can be aggravated as explained by Dr. Steinman’s medical theory on “how
the components of the [Pentacel] vaccine can drive an interferon response” leading to
“worsening neuroinflammation in H[.]H.” and whether this theory satisfies the Loving standard.
Steinman Rep. at 9; Steinman Reply at 3; see Sharpe, 964 F.3d at 1083.
B. Logical Sequence of Cause and Effect under Loving Prong Five
Under Loving prong five, a petitioner must show by preponderant evidence “a logical
sequence of cause and effect showing that the vaccination was the reason for the significant
aggravation.” Loving, 86 Fed. Cl. at 144. For satisfying the fifth Loving prong, “medical records
and medical opinion testimony are favored in vaccine cases, as treating physicians are likely to
be in the best position to determine whether ‘a logical sequence of cause and effect show[s] that
the vaccination was the reason for the injury.’” Capizzano v. Sec’y of Health & Hum. Servs., 440
F.3d 1317, 1326 (Fed. Cir. 2006) (quoting Althen, 418 F.3d at 1280).
The Special Master found “[p]etitioners have not presented evidence demonstrating that
H.H. experienced a vaccine-associated significant aggravation of his interferonopathy, signs of
which had already begun to manifest by the time he received his Pentacel vaccine. They do not
point to any testing or clinical signs that suggest vaccine causation.” SM Dec. at 68. The
Special Master continued, “[petitioners] do not point to any testing or clinical signs that suggest
vaccine causation. Instead, they assert that because H.H.’s deterioration occurred close-in-time
to his vaccinations, and because no alternate explanation exists, then the vaccines ‘did cause’ a
significant aggravation of H.H.’s condition.” Id. The Special Master also found the elevated
transaminase levels and lack of a severe local reaction are not supported by petitioners’ causation
theory. Id. (“[T]he records contain evidence supporting the opposite position—that the vaccines
did not affect his condition.”).
The Special Master further discredited “several of H.H.’s treating doctors [who] opined
that the vaccines he received caused his condition.” Id. at 69. For instance, the Special Master
discredited Dr. Hollis, H.H.’s treating physician, who concluded H.H.’s “rapid decline can be
attributed to receiving the vaccinations on October 17, 2013 and October 23, 2013,” because
“[s]he did not articulate a theory of causation.” Id. Additionally, the Special Master discredited
Dr. Marks, H.H.’s treating neurologist, who opined the vaccines H.H. received caused his
condition, because his theory of causation—a theory of molecular mimicry which was
abandoned and replaced by Dr. Steinman’s theory—was unpersuasive. Id. 69–71 (“Dr. Marks’
inability to persuasively articulate a theory of causation caused me to afford his opinion less
weight.”).
Petitioners allege in their third objection the Special Master “devalued the expert opinion
of petitioners’ [sic] expert” who “provided evidence sufficient to satisfy [p]rongs 5 and 6 of
Loving when discussing whether the Pentacel vaccination significantly aggravated H.H.’s injury,
which would also satisfy Althen.” Mot. for Review Mem. at 18. Petitioners argue the Special
Master’s suggestion all symptoms in H.H.’s medical record should be explained by the causation
theory is incorrect. Tr. 80:2–21. Petitioners explained they are “not seeking to prove what
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raised his transaminases . . . . [They] have put forth a . . . medical theory that the vaccination
caused an AGS-like interferonopathy and damage.” Id. at 80:13–21. The government argues the
mere showing of a proximate temporal relationship between the vaccine and injury is insufficient
to satisfy Loving prong five. Resp’t’s Resp. at 11 (citing Moberly, 592 F.3d at 1323). The
government further argues there are symptoms Dr. Steinman’s theory does not explain. Tr. at
81:7–12 (“[THE GOVERNMENT]: [T]hey haven’t shown that there was a vaccine reaction
after the Pentacel to fit in Dr. Steinman’s theory. [T]he liver enzymes . . . there’s nothing about
petitioners’ theory that would explain that.”).
The Special Master’s underlying assumption—“H.H.’s presentation” can be attributed to
an “expanded understanding of the AGS phenotype”—devalued evidence supporting significant
aggravation. SM Dec. at 56; see supra Section VI.B. The Special Master found “petitioners
have not presented evidence demonstrating that H.H. experienced a vaccine-associated
significant aggravation of his interferonopathy, signs of which had already begun to manifest by
the time he received his Pentacel vaccine.” SM Dec. at 68. In Sharpe, a case with a pre-existing
condition caused by a genetic mutation, there was a similar assumption, and the special master
found petitioner failed to meet Loving prong five “because, in part, ‘it is quite likely that [the
injury] in fact began prior to vaccination.’” Sharpe, 964 F.3d at 1086. The Federal Circuit
rejected this reasoning stating, “[a] significant aggravation claim, by definition, requires a
petitioner to have a pre-existing injury. . . . Thus, that [petitioner] experienced some [injury]
before receiving her vaccination should have no negative effect on [p]etitioner’s case.” Id. The
government’s experts, Drs. McGeady and Barañano, whom the Special Master credits, both
opined “there is variability in AGS presentation” including variety of symptoms (or lack thereof)
and severity, but the Special Master’s decision does not contemplate a mild case of AGS with the
vaccine worsening the disorder because the Special Master attributes all injury to the underlying
genetic mutation. SM Dec. 58 (“Both Dr. McGeady and Dr. Barañano opined that there is
variability in AGS presentation . . . .”), 68 (finding no signs of significant aggravation because
signs “had already begun to manifest by the time [H.H.] received his Pentacel vaccine”).
Characterizing H.H.’s injury as AGS or AGS-like and attributing all symptoms of an “expanded
understanding of the AGS phenotype” to a “severe outcome” because of his genetic mutation
caused the Special Master’s finding on Loving prong five to be arbitrary and capricious because
it ignored vaccine aggravation. SM Dec. at 58; see Knudsen, 35 F.3d at 550; Sharpe, 964 F.3d at
1086.
In the prong-four analysis, the Special Master rejected Dr. Steinman’s theory because it
does not explain “massively exaggerated” response or how levels “remained elevated for years
after vaccination.” SM Dec. at 66. While a pre-existing condition “should have no negative
effect on the petitioners’ case,” the pre-existing condition cannot be completely ignored as the
severity and symptoms of a purely genetic disorder is instructive in determining if a vaccine
aggravated the pre-existing condition. See Knudsen, 35 F.3d at 550; Sharpe, 964 F.3d at 1086.
Here, “a significant aggravation claim, by definition, requires a pre-existing condition,” and the
Special Master ignored the fact “persistent elevation of H.H.’s neopterin levels” and “elevated
levels of [interferon]-alpha” is diagnostic for AGS, the disorder the Special Master found H.H. to
have. SM Dec. at 53–55, 57, 68–69; see Sharpe, 964 F.3d at 1086; supra Section VI.B. The
Court finds this to be erroneous because the Special Master ignored the possibility of vaccine
aggravation. See Knudsen, 35 F.3d at 550; Sharpe, 964 F.3d at 1086.
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When the Special Master found the medical records failed to support a
vaccine-aggravated injury, the Special Master pointed to the lack of a local reaction and elevated
transaminases as evidence against a vaccine aggravated injury. SM Dec. at 69 (“Petitioners have
not explained how this finding fits into their causation theory. Dr. McGeady opined that there
was no medical literature supporting such a connection.”). A petitioner “need not explain other
symptoms” associated with the pre-existing condition but rather a petitioner must prove “the
vaccination caused his significant aggravation.” Id.; Knudsen, 35 F.3d at 550; Loving, 86 Fed.
Cl. at 144. In Knudsen, a case reviewing whether a vaccine or a viral infection caused the
petitioner’s injury, the Federal Circuit held “petitioners need not explain all other symptoms or
injuries by reference to the . . . vaccination, and the issue in vaccine cases is not to diagnose all
the injuries and symptoms of the child in order to ascertain whether the diagnosis is [vaccine] or
something else.” Knudsen, 35 F.3d at 550. By requiring petitioners to explain all symptoms (or
lack thereof), the Special Master ignored the crux of a significant aggravation claim—“a
significant aggravation claim, by definition, requires a petitioner to have a pre-existing injury,”
and other symptoms could be attributed to the pre-existing condition, not the vaccine-aggravated
injury. See Sharpe, 964 F.3d at 1086. While the Special Master required petitioners’ medical
theory to account for all symptoms, the Vaccine Act does not impose such a burden but only
requires showing the vaccination “caused significant aggravation,” and accordingly the Court
finds this to be error. SM Dec. at 68–69; see Knudsen, 35 F.3d at 550 (“[P]etitioners need not
explain all other symptoms or injuries by reference to the . . . vaccination, and the issue in
vaccine cases is not to diagnose all the injuries and symptoms of the child in order to ascertain
whether the diagnosis is [vaccine] or something else.”); Loving, 86 Fed. Cl. at 144 (holding a
petitioner must show “a logical sequence of cause and effect showing that the vaccination was
the reason for the significant aggravation”).
Evidence for Loving prongs four and five often overlap. Knudsen, 35 F.3d at 548 (“This
logical sequence of cause and effect must be supported by a sound and reliable medical or
scientific theory.” (internal quotations omitted)); Moriarty v. Sec’y of Health & Hum. Servs., 844
F.3d 1322 (Fed. Cir. 2016) (“There is ‘no reason why evidence used to satisfy one of the [Althen]
prongs cannot overlap to satisfy another prong.’” (quoting Capizzano, 440 F.3d at 1326)). The
Federal Circuit has suggested “in certain cases, a petitioner can prove a logical sequence of cause
and effect between a vaccination and the injury . . . with a physician’s opinion to that effect
where the petitioner has proved that the vaccination can cause the injury . . . and that the
vaccination and injury have a close temporal proximity[.]” Sharpe, 964 F.3d at 1086 n.5 (citing
Moriarty, 844 F.3d at 1333 (emphasis added)). The Special Master dismissed the physicians’
opinions concerning whether the vaccine caused H.H.’s injury because they “could not articulate
a medical theory.” SM Dec. at 69 (“[Dr. Hollis] did not articulate a theory of causation”), 71
(“Dr. Marks’ inability to persuasively articulate a theory of causation caused me to afford his
opinion less weight.”). The replacement of the theory after the entitlement hearing, however,
should not devalue the treating physicians’ opinion of H.H.’s injury being aggravated by the
vaccine because prong five does not require a treating physician to opine on a medical theory to
find their testimony persuasive—only prong four requires opinion on a medical theory. See
Andreu, 569 F.3d at 1375 (“[T]reating physicians are likely to be in the best position to
determine whether a logical sequence of cause and effect show[s] that the vaccination was the
reason for the injury.”); Loving, 86 Fed. Cl. at 144 (holding a petitioner must show “a logical
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sequence of cause and effect showing that the vaccination was the reason for the significant
aggravation”); Pet’rs’ Ex. 66 at 3, ECF No. 43–3 (Dr. Hollis Affidavit) (“It is my opinion that
H.H.’s severe and rapid developmental regression is unusual for a previously healthy child.
Many diagnoses have been evaluated and ruled out . . . . It seems to me that his rapid decline can
be attributed to receiving the vaccinations on October 17, 2013 and October 23, 2013.”); Pet’rs’
Ex. 67 at 3–4, ECF No. 43–4 (Dr. Marks Affidavit) (“It is my opinion that it was quite unusual
for a previously asymptomatic patient to develop such severe and rapidly progressing dystonia
with encephalopathy at this age. . . . I have concluded that H.H.’s exposure to the fifteen (15)
month vaccines was within a reasonable medical probability, the most likely trigger for him to
develop rapidly progressing dystonia with encephalopathy to this degree.”). Loving prong five is
“supported” by Loving prong four, and the Court finds the Special Master’s analysis of Loving
prong four to be arbitrary and capricious. See Knudsen, 35 F.3d at 548 (“This logical sequence
of cause and effect must be supported by a sound and reliable medical or scientific theory.”);
supra Section VII.A. As the record contains evidence of the treating physicians opining H.H.’s
injuries were aggravated by the vaccinations, the Special Master’s Loving prong five is not
supported by the record, and the Court must remand the case. Dr. Hollis Affidavit at 3; Dr.
Marks Affidavit at 3–4; see Paluck, 786 F.3d at 1380 (“Where, as here, a special master . . .
makes factual inferences wholly unsupported by the record, the Court of Federal Claims is not
only authorized, but obliged, to set aside the [S]pecial [M]aster’s findings of fact and conclusions
of law.”). The Court makes no finding on whether logical sequence is proven and leaves open
the question of whether Loving prong five is met in light of Dr. Steinman’s report on significant
aggravation to the Special Master on remand. See Sharpe, 964 F.3d at 1383; Knudsen, 35 F.3d at
548.
C. Proximate-Temporal Relationship under Loving Prong Six
Prong six of the Loving test requires “a showing of a proximate temporal relationship
between the vaccination and the significant aggravation.” Loving, 86 Fed. Cl. at 144. “[T]he
proximate temporal relationship prong requires preponderant proof that the onset of symptoms
occurred within a timeframe for which, given the medical understanding of the disorder’s
etiology, it is medically acceptable to infer causation-in-fact.” de Bazan v. Sec’y of Health &
Hum. Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008).
Petitioners’ third objection argues Dr. Steinman’s medical theory provides a three-week
interval in which symptoms worsened. Mot. for Review Mem. at 18; Tr. at 88:8–17
(“[PETITIONERS]: [I]t’s petitioners’ contention that Dr. Steinman’s report and the literature he
provided sufficiently demonstrates that H.H.’s onset was within a medically reasonable time
frame, and we contend that there were early signs immediately after the Pentacel vaccine . . . and
that the completion of his damage was done in approximately three weeks.”). The government
argues Dr. Steinman’s theory is not sufficiently supported. Tr. at 87:8–10 (“[THE
GOVERNMENT]: Dr. Steinman [is] just saying that three weeks, without the proper support,
doesn’t meet petitioners’ burden.”).
In her two-page analysis regarding proximate-temporal relationship, the Special Master
found petitioners failed to prove either “H.H.’s type I interferonopathy either began or was
significantly aggravated three weeks after the Pentacel vaccin, or . . . [p]etitoners have
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preponderantly established that the three weeks post vaccination is a medically acceptable onset
interval.” SM Dec. at 74. The Special Master noted Dr. Steinman’s three-week interval is based
on a direct causation claim theory because there was not “any symptomatology related to an
interferonopathy” until “three weeks after the Pentacel immunization on October 23, 2013.” Id.
at 72. The Special Master concluded Dr. Steinman’s “opinion regarding the appropriateness of
the onset interval” was based on an onset theory, not a significant aggravation theory. Id. Dr.
Steinman explains in his reply, however, “I have covered the two alternatives in describing either
a theory based on direct causation or on significant aggravation. The onset of
neuroinflammation within [three] weeks of the October 23, 2013 immunizations with Pentacel is
consistent with [Schonberger] and [Bennetto & Scolding], which cover related
neuroinflammatory conditions of the peripheral . . . and central nervous systems[.]” Steinman
Reply at 3. Petitioners asserted Dr. Steinman’s medical theory provides a three-week onset for
both direct causation and significant aggravation. Tr. at 88:8–11 (“[PETITIONERS]: [I]t’s
petitioners’ contention that Dr. Steinman’s report and the literature he provided sufficiently
demonstrated that H.H.’s onset was within a medically reasonable time frame, and we contend
that there were very early signs immediately after the Pentacel vaccine, within days, and that the
completion of his damage was done in approximately three weeks.”). The Special Master does
not consider Dr. Steinman’s theory relating to significant aggravation because the Special Master
found her “determination in this case is contrary to Dr. Steinman’s” opinion regarding the onset
of symptoms. SM Dec. at 72. The Special Master’s characterization of Dr. Steinman’s theory to
only include direct causation when he opined “on significant aggravation” is arbitrary and
capricious because the Special Master did not consider Dr. Steinman’s theory on significant
aggravation in the record. See Steinman Reply at 3; Hines, 940 F.2d at 1528 (“If the [S]pecial
[M]aster has considered the relevant evidence of record, drawn plausible inferences and
articulated a rational basis for the decision, reversible error will be extremely difficult to
demonstrate.”).
The Court finds, as discussed supra Section VII.A, the Special Master’s Loving
prong-four analysis was arbitrary and capricious and because “a temporal relationship is closely
related to the underlying medical theory” required by prong four, the Court also reviews for error
the causation analysis under Loving prong six. See Capizzano, 440 F.3d at 1326. 11 Despite the
Special Master stating Dr. Steinman did not opine on significant aggravation, the Special Master
did continue to analyze Loving prong six in light of significant aggravation. SM Dec. at 73
(“Naves . . . does not support the position that an interferonopathy would begin or become
significantly aggravated either on the same day or within one or two days after a trigger.”). The
Special Master concluded, “I do not find H.H.’s type I interferonopathy either began or was
significantly aggravated three weeks after the Pentacel vaccine[,]” but did not provide an
analysis to discuss the timeline of H.H.’s injuries or whether H.H.’s injuries were significantly
aggravated. Id. at 74. The Special Master did not “articulate a rational basis for her decision”
nor is her decision supported by the record because the Court finds her analysis under Loving
11
In Pafford, a case involving the development of Still’s disease following vaccination, the Federal Circuit
emphasized “evidence demonstrating petitioner’s injury occurred within a medically acceptable time frame bolsters
a link between the injury alleged and the vaccination at issue under the ‘but-for’ prong of causation analysis.”
Pafford v. Sec’y of Health & Hum. Servs., 451 F.3d 1352, 1358 (Fed. Cir. 2006). Finding a temporal relationship is
also closely related to the underlying medical theory of the injury. Capizzano, 440 F.3d at 1326 (“We see no reason
why evidence used to satisfy one of the [Loving] prongs cannot overlap to satisfy another prong.”).
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prong four to be arbitrary and capricious. See Hines, 940 F.2d at 1528; see also Paluck, 786
F.3d at 1380 (“Where, as here, a special master misapprehends a petitioner’s theory of causation,
misconstrues his medical records, and makes factual inferences wholly unsupported by the
record, the Court of Federal Claims is not only authorized, but obliged, to set aside the [S]pecial
[M]aster’s findings of fact and conclusions of law.”); Andreu, 569 F.3d at 1375 (concluding that
a special master erred in disregarding probative testimony from a petitioner’s treating
physicians). The Court remands and leaves the ultimate conclusion to the Special Master
regarding whether there was a proximate-temporal relationship in light of Dr. Steinman’s
opinion stating aggravation would occur within three weeks and whether this theory satisfies
Loving prong six. See Steinman Reply at 3 (“I have covered the two alternatives in describing
either a theory based on direct causation or on significant aggravation”); see also Capizzano, 440
F.3d at 1326 (“We see no reason why evidence used to satisfy one of the [Loving] prongs cannot
overlap to satisfy another prong.”).
VIII. Conclusion
For the foregoing reasons, the Court SUSTAINS the Special Master’s decision relating to
the influenza and pneumonia vaccinations as petitioners did not meet their burden of proof under
the Loving/Althen frameworks. The Court VACATES the Special Master’s decision finding
Pentacel did not significantly aggravate H.H.’s type I interferonopathy because the Special
Master erred by assuming H.H.’s injury and diagnosis was purely genetically caused before
starting the Loving analysis. The Court therefore GRANTS IN PART petitioners’ motion for
review and REMANDS to the Special Master to determine whether petitioners can satisfy
Loving prongs four, five, and six for significant aggravation by Pentacel.
IT IS SO ORDERED.
s/ Ryan T. Holte
RYAN T. HOLTE
Judge
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